TW201242964A - 5,5-bisubstituted-2-iminopyrrolidinederivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to 5, 5-bisubstituted-2-iminopyrrolidine derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel 5, 5-bisubstituted-2-iminopyrrolidine derivatives presented by formula (I), the uses for treatment especially for thrombin receptor antagonists, in which each substitute group of general formula (I) is as defined in the specification.

Description

201242964 VI. Description of the Invention: [Technical Field] The present invention relates to a novel 5,5-disubstituted-2-iminopyrrolidine organism, a preparation method thereof, and a pharmaceutical composition containing the same And its use as a therapeutic agent, in particular as a thrombin receptor antagonist. [Prior Art]

Thrombotic diseases are currently the leading cause of high rates of cardiovascular disease and high mortality worldwide. Arterial thrombosis can cause a variety of acute symptoms including acute coronary syndrome, ischemic stroke/transient cerebral ischemia, and peripheral arterial disease. These symptoms are caused by rupture of atherosclerotic plaque or damage to the vascular endothelial cells, which in turn induces the formation of arterial blood (four) plugs, which in turn leads to insufficient supply of sputum. Platelets play a very important role in the formation of arterial thrombosis. In this pathological process, rupture of atherosclerotic plaque or damage of vascular endothelial cells can cause vascular injury. Under the action of various platelet activating factors such as thrombin, thromboxane 2 and ADP, the platelet activation mechanism is out of control. and then

Causes a large number of platelets to initiate and aggregate, and then forms a thrombus under the guidance of Gnb/IIla receptor, which ultimately blocks blood flow. Among these platelet agonists, thrombin (thr〇rabin) acts as The most potent blood plate activator, which activates platelets and induces aggregation by interacting with members of the G-protein-coupled receptor family, thereby achieving clotting and physiology. Activated receptors (PARs) belong to the G protein-coupled receptor family, which is 95255 4 201242964 widely expressed in various cells in the cardiovascular system, such as platelets, vascular endothelial cells, and vascular smooth muscle cells.

Under normal physiological conditions, gorge a, transvascular endovascular stability, and inflammatory response under pathological conditions, money and arteriosclerotic squamous scales of various physiological processes' play a key role in it. This family of receptors uses a unique mechanism to achieve the activation process: thrombin (thr〇mbin) that binds to PARs hydrolyzes the original n-terminus in the extracellular domain of the PARs receptor to form a new N The newly formed N-terminus binds to PARs in a manner that binds to PARs to induce receptor activation, thereby enabling signal transduction. It has been confirmed that the PARs family contains four receptor subtypes, including PAR1, PAR2. , PAR3 and PAR4. In addition to PAR2 as a receptor for trypsin (=ypsin) and tryptase (tryptase), the other three subtypes can be activated by binding to thrombin and are therefore considered to be the major thrombin. Thrombin receptors, in which PAR1 is a high-affinity thrombin receptor that is activated at lower concentrations (less than nanomolar concentrations) of thrombin. In contrast, PAR4 is a low-affinity thrombin. The receptor is involved in the activation and transmission of thrombin signals only under the conditions of more prolific thrombin. Similar to PAR1, although PAR3 is also a high-affinity receptor, it usually does not activate the signaling alone. No., but as a co-receptor in combination with PAR4 to increase the activity of PAR4 and achieve corresponding biological functions (see

Ho-Sametal; Current Pharmaceutical Design, 2003, 9, 2349-2365). As the most important condensing jk enzyme receptor, PARI is widely expressed in many cells and tissues in human body, including platelets, endothelial cells, blood vessels or gas 95255 5 201242964 tube smooth muscle 'inflammatory cells (macrophages, lymphocytes) , fibroblasts, nerve cells, cardiovascular and skeletal muscle cells. In addition to cardiovascular disease, elevated levels of PAR1 can be observed in a variety of pathological conditions such as trauma, inflammation, and various tumor cells. In addition, PAR1 can also activate receptor tyrosine kinase activity by G-protein signal cross-linking and affect the corresponding 彳§ cascade, thereby regulating cell proliferation and metastasis (see DerianCK, et al; Sighing people 2003' 12: 209-21). These are further foretelling? Eight can be used as a therapeutic target for a variety of diseases. It is seen that a large number of non-peptides for the treatment of arterial thrombosis diseases are being pre-clinical or clinical trials with inhibitors. In the early stages of development, oral antiplatelet drugs are mainly used to regulate the platelet synthesis process of blood test A2 (such as aspirin aspirin) or P2Ylz ADp receptor-mediated platelet activation process (such as tielQpidine (Qian Yi)) There is no direct inhibition of the clotting enzyme-platelet activation pathway by H from the PAR1 receptor (DaviG, etal) fine 7/shot, win 357. 2482 2494). At the same time, since both can weaken or interfere with the process of platelet aggregation induced by gelatin, which may have an effect on the normal hemostasis, the rhetoric of the treatment of silk is increased. In contrast, the antagonist developed with PARI as a dry point directly targets thrombin-blood, which is a process that can perform a more comprehensive and direct inhibition of platelet activity4, while directly reducing thrombosis and acute deficiency. Blood symptoms! 2 Risks In addition to the normal coagulation-hemostasis mechanism, inhibition of PAR1 can reduce the risk of gold withdrawal during treatment (see 95255 6 201242964 See Coughlin SR.; / 7^0 calendar and status , 2〇〇5, 3: 18〇〇, 1814). More importantly, the antagonists of sputum do not affect the normal clotting activity of Thrombin itself. In special emergency situations, 'coagulation enzymes can still pass # inducing platelet activation and aggregation by brain money. , play the normal condensate function. Therefore, antiplatelet drugs developed by inhibiting pARi have not only improved the therapeutic effect and specificity, but also reduced possible side effects, and have become an ideal drug for treating arterial thrombosis diseases. A number of patent applications for thrombin receptor antagonists have been disclosed, including PCT patent applications, such as WO2002085855, WO2005084679, WO2004078721, and WO2006051623, which disclose a series of 2-imido 0-pyrrol derivatives. The present invention has been designed to have a compound represented by the general formula (I), and it has been found that a compound having such a structure exhibits excellent thrombin receptor inhibitory activity. SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a novel pyridazinone derivative represented by the general formula (I), and tautomers and enantiomers thereof. , diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs,

Of which: 7 95255 (I) 201242964

Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further substituted with one or more substituents of Ra as desired; Y is selected from -CR12- or N atom; L is selected from -CR13R14- or -(CH〇„-; R1, R2 and R3 are each independently selected from the group consisting of a hydrogen atom, a dentate, a thiol group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring. Base, aryl, heteroaryl, -C(0)0R15, -0C(0)R15, -0(CH2)nC(0)0R15, -(CH2)nC(0)0R15, -C(0)R15 , -NHC(0)R15, -S(0)PR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 or -S(0)0NR16R17, wherein the alkoxy group, the hospital base, the ring burn a group, a heterocyclic group, an aryl group or a heteroaryl group, further optionally one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, Heteroaryl, -C(〇)〇R15, -OCCO)!^, -0(CH〇nC(0)0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0 Substituting a substituent of R15, -S(0)pR15, -NR16R17, -〇C(0)NR16R17 or -C(0)NR16R17; R1 and R2 or R2 and R3 together with the attached carbon atom form an aryl group Where the aryl group is further protected by one A plurality of selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R15, -〇c(〇)R15 , -〇(CH2)nC(0)OR15, -(CH2)„C(0)0R15, -c(〇)R15, -NHC(9)R15, -S(0)PR15, -NR16R17, _〇C(0)NR16R17 Substituting a substituent of -c(〇)NR16R17 or -S(0)0NR16R17; R4 and R5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl a group wherein the alkyl, alkoxy, cycloalkyl, 8 95255 201242964 heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl , aryl, heteroaryl, -C(〇)〇R15, -0C(0)R15,-0(CH2)„C(0)0R15, —(CH2)nC(〇)ORi5, _c(8)Rl5, -NHC( 0) R15, -S(0)PR15, -NR16R17, _〇C(〇)NR16Rn, _c(〇)NRl6Rl7 or -S(0)0NR16R17 substituted by a substituent, or R4 and R5 are bonded to a carbon The atoms together form a cycloalkyl group, wherein the cycloalkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl Substituted by a heterocyclic group or a substituent of -NR16R17 •; R6 is selected from a hydrogen atom 'hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, -C(0)0R15, -C( 0) R15 or -C(0)NR16R17, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, Substituted by a substituent of an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group; R may be the same or different 'each independently selected from a nitrogen atom, a thiol group, a cyano group, a nitro group, a decyl group, an alkoxy group Base, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(〇)〇R15, -〇C(〇)R15, -0(CH2)„C( 0) 0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, _S(0)PR15, -NR16R17, -0C(0)NR16R17, -c(〇)NR16R17 Or -s(o)onr16r17, wherein the decyl group, the alkoxy group, the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are further selected from one or more as needed Element, hydroxyl, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyalkane Base, -C(0)0R15, -0C(0)R15, -〇(CH2)„C(0)OR15,~(CH2)nC(0)0R15,-C(0)R15, 9 95255 201242964 -NHC (0) Substituting for a substituent of R15, -S(〇)pR15, _NRi6R17, -0C(0)NR16R17, -C(〇)NR16R17 or -S(0)0NR16Rn; R12 is selected from a hydrogen atom, a halogen, a hydroxyl group, Cyano, nitro, alkoxy, alkyl, dilute, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15, -〇C(0)R15, - 〇(〇H2)nC(0)OR15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -s(〇)PR15, -NR16R17, -〇c(〇 NR16R17, -C(0)NR16R17 or -S(0)〇NR16R17, wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further selected by one or more From halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(〇)〇R15, -0C(0)R15, -0 (CH2)nC(0)0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -〇c(〇)NR16R17 Substituting a substituent of -C(〇)NRl6R17 or -S(0)0NR16R17; R13 and R14 are each independently selected from an alkyl group or a halogen, wherein the alkyl group Further required to be substituted by one or more substituents selected from the group consisting of a hydrazine, a hydroxy group, a cyano group or a nitro group; R15 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein The alkyl group, ring group, heterocyclic group, aryl group or heteroaryl group is further substituted by one or more substituents selected from the group consisting of a south, a hydroxyl group, a cyano group, a nitro group, an alkoxy group or an alkyl group, as needed. ; R16 and R17 are each independently selected from the group consisting of a gas atom, a sulfonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein a Wei group, a gas group, a cycloalkyl group, a heterocyclic group; The aryl, aryl or heteroaryl group is further optionally one or more selected from the group consisting of halogen, thiol, cyano, thio, alkoxy, alkyl, cycloalkyl, 95255 10 201242964 heterocyclyl, aryl, Heteroaryl, _C(0)0R15, -〇C(0)ti15 ' _O(CH2)„C(0)0R15, _(CH2)nC(0)0R15, -C(0)R15, -NHC(0 Substituting a substituent of R15, -S(0)PR15, -NR18R19, -0C(0)NR18R19, -C(0)NR18R19 or -s(o)onr18r19; or, R16 and R17 are bonded to a nitrogen atom Forming a heterocyclic group wherein the heterocyclic group contains one or more N, hydrazine S(0)p heteroatom' and the heterocyclic group is further protected by one or more halogens, thiols, cyano groups, nitro groups, alkoxy groups, alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, Heteroaryl, hydroxyalkyl, _c(0)0Rl5, -0C(0)R15, -〇(CH2)nC(0)OR15, -(CH2)nC(0)0R15, -c(〇)R15, Substituted by a substituent of -NHC(〇)R15, -S(0)PR15, -NR18R19, _0C(0)NRl8Rl9, -c(〇)NR18R19 or -S(0)0NR18R19; 彳R are each independently selected from a ruthenium atom , halogen, alkyl, cycloalkyl, heterobasic, aryl or heteroaryl; m is selected from the group 2 or 3; φ η is selected from 1' 2 or 3; and fluorene is selected from 0 ' 1 or 2. A preferred embodiment of the present invention, a compound of the formula (1) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (II) or a pharmaceutically acceptable compound thereof salt:

11 95255 201242964 wherein z Y is selected from -□{12_ or N atom; L is selected from -CR13R14- or -(CH2)m-;

R1, R^R3 are each independently selected from the group consisting of a hydrogen atom, a self group, a sulphur group, an alkoxy group, a decyl group, an alkenyl group, a silk group, a fluorenyl group, a fluorenyl group, a hydrazino group -00(9)^, (5) nC -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)Rl5, _s(〇)pRl5, _NRl6Rl7, -〇(10)Nmc_ms_NRl6Rl7, wherein the alkoxy group, the hospital base, the secret group, the miscellaneous The cyclic group, the aryl group or the heterofilament may be further further _ or more (four) from i, thiol 'cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl Base, ~C(〇)〇r15, 〇c(〇)r15, -0(CH2)nC(0)0R15, -(CH2)nC(0)0R15,~c(〇)r15-nhc(〇)r15 , -scom15,, 13⁄417, -_) heart 17 or < (substitution of 161^17 substituents; R and R2 or R2 and R3 together with the attached carbon form an aryl group, wherein the aryl group is required - Steps are selected from one or more selected from the group consisting of _, thiol, nitro, ketone, alkoxy H, ketone, heterocyclyl, aryl, heteroaryl, 'C(0)0R > - 〇 C(〇)R15. -〇(CH2)nC(〇)〇R15, -(CH2)nC(0)0R15 'C(0)R, _NHC(〇)R15, -S(0)PR15,-nr16r17, -〇c(〇)NR16R17, ~C(0)M16R17 or ~S(〇)〇NRl6Rn Substituted; R and R5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterotyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, hetero The cycloaryl or heteroaryl is further optionally selected from one or more selected from the group consisting of halogen, thiol, benzo, cyano, alkyl, aryl, heteroaryl, -C(0)0R15, 12 95255 201242964 -0C (0) R15, -0(CH2) „C(0)0R15, -(CH2)nC(〇)〇Ri5, _c(〇)R,5, -NHC(0)R15, -S(0)PR15, Substituting a substituent of -NR16R17, _〇C(0)NR16r17, -c(〇)NR16R17 or -s(o)onr16r17; or R4 and R5 together with a carbon atom to which they are bonded form a cycloalkyl group, wherein the ring The alkyl group is further optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic or -NR16R17; R6 is selected from a hydrogen atom , hydroxy, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, -c(o)or15, -c(o)r15 or -c(o)nr16r17, wherein the alkyl group, oxygenated a group, a cycloalkyl group, an aryl group or a heteroaryl group, as required, one or more selected from the group consisting of halogen, hydroxy, nitro, Substituted by a substituent of a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group; R7, R8, R9, R1D and R11 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a decane group. Alkyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15, -0C(0)R15, -0(CH〇nC (0)0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -0C(0)NR16R17, -C(0 Or NR16R17 or -S(0)0NR16R17, wherein the decyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further protected by one or more Selected from a hydroxyl, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl, -C(0)0R15, -0C (0 ) R15, -〇(CH2)nC(0)OR15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -s(〇)pR15, -NR16R17, -〇 Substituted by a substituent of C(〇)NR16R17, -C(0)NR16R17 or -s(o)onr16r17; 13 95255 201242964 or 'R9 and IT are bonded to a carbon atom to form a heterocyclic group, an aryl group or a hetero Aryl group The base or the heterofilament is further selected from one or more selected from the group consisting of: self-priming, minus, cyano, nitro, flammable, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, Aryl, heteroaryl, -C(〇)〇R15, -0C(0)Rl5, _〇(CH〇nC(〇)〇R,5, _(CH ^ , -c(o)Ri5, -NHC (0) Substituting substituents of Ri5, _s(0)pRl5, -NR, 6Rl7-〇c(7))nr16r17, -C(0)NR16R17 or -S(0)0NR16R17; R12 is selected from a hydrogen atom, a hydroxyl group, a , cyano, nitro, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)〇R15. -0C(0)R15 -0(CH2)„C(0)0R- . -(CH2)nC^〇R-. -C(0)R15, -NHC(0)R15, -S(〇)pR15,-NR16R17' —〇 c(〇)nr, 6r17, -C(0)NR16R17 or -S(0)〇NR16R17, wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are further required as needed One or more 2 from halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15, -OC (〇; ) R15, -0(CH2)nC(0)0R15, -(CH2)„C(0)0R15, -C(〇)Ri5, NHC(〇)Rl5, -S (0) Substituting substituents of PR15, -NR16R17, -〇c(〇)NR16R17, -C(〇)nr16r" or -S(0)0NR16R17; R13 and R14 are each independently selected from an alkyl group or a halogen, wherein The calcination is further substituted by one or more substituents selected from a hydroxyl group, a thiol group, a cyano group or a decyl group; R15 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from the group consisting of dentate, hydroxyl, cyano, jing, calcined 95255 14 201242964 or Substituted by a substituent of an alkyl group; R and R17 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group , J 哀 alkyl, heterocyclic, aryl or heteroaryl, further optionally one or more selected from the group consisting of _ s, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl, _C(〇)〇R15, _〇C(〇)R15, -0(CH2)nC(〇)〇R15 x -(CH2)nC(〇)〇R15 χ -C( 0) R15' -NHC(0)R15 ' -S(0)PR15, -NR18R19, -〇c Substituting (n) a substituent of nr18r19, -C(〇)NR18r19 or ?-s(o)onr18r19; or 'R16 and R17 form a heterocyclic group with a nitrogen atom bonded thereto, wherein the heterocyclic group contains one or a plurality of N, hydrazine or s(〇)p heteroatoms, and the heterocyclic group is further further protected by one or more dentates, hydroxyl groups, cyano groups, nitro groups, alkoxy groups, alkyl groups, cycloalkyl groups, Cyclo, aryl, heteroaryl, hydroxyalkyl, -C(〇)〇R15, —〇C(8)Ri5, 〇(CH2)nC(9)〇Rl5, _(CH2)nC(0)0R15, -C(〇) Substituents of Ri5, _NHC(〇)Rl5, _s(8), _nr18r19, -0C(0)NR18R19, -C(〇)NR18R19 or -S(0)0NR18R19 are taken as W; R18 and R19 are each independently selected from a hydrogen atom , halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl. m is selected from 1, 2 or 3; η is selected from 1, 2 or 3; and Ρ is selected from 0, 1 or 2. A preferred embodiment of the present invention, which is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is selected from a 5- or 6-membered heteroaryl group, preferably 15 95255 201242964 is a beta-Byloyl group. Or "than." Set the foundation. A preferred embodiment of the present invention, which is a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein &4 and R5 are selected from an alkyl group or an aryl group. ', a preferred embodiment of the present invention, a compound of the formula (1) or a cola salt thereof, which allows the trans 4 and R 5 together with the carbon atom to be bonded to form a cyclopropyl group. A preferred embodiment, a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein γ is selected from a hydrogen atom. From a preferred embodiment of the invention, a compound of the formula (1) or a pharmaceutically acceptable salt thereof R2 is selected from a hydrogen atom or a dentate. A pharmaceutically acceptable salt, wherein L is selected from -(CH2)n-, πι is 1. The fg compound of the present invention includes, but is not limited to: a compound number structure name 1 -------- HBr ' 1_ (3,5 _.-tert-butyl-4-phenyl)-2-(3'-imino-5',6'-didecyloxy - snail [cyclopropanone-1, Γ-iso-α 弓布朵琳] -2'-yl) acetamidine hydrogen oxalate 2 [. sentence > ^., HBr 〇 1-(3-tert-butyl- 4-decyloxy-5-morpholinyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ-isoindole]- 2'-yl)ethyl g and hydrobromide salt of the present invention, a compound of the formula (1) or its 16 95255 201242964

3: Right &gt;^. , HBr 1-(3-tert-butyl-4-methoxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ- Isoporphyrin]-2'-yl)ethanone hydrobromide 4 ΝΗ \ ΗΒΓ ΒΓ 1-(3-Mo-5-tert-butyl-4-phenylphenyl)-2-(3imino) -5',6'-dimethoxyspiro[cyclopropane-1, fluorene-isoporphyrin]-2'-yl)ethanone hydrobromide 5 ΝΗ \ :〇^Ν&gt;^ HBr V〇ό 2-[8-tert-Butyl-6-[2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ-isoindole 0-lin]-2 '-yl) ethyl aryl]_ 2,3-di-argon-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 6 ΝΗ \ Co^^o HBr _ynJ 1-(8- tert-Butyl-4-ethyl-2,3-diindole-1,4-benzoxazin-6-yl)-2-(3'-imino-5',6'-didecyloxy - Spiro [cyclopropane-1, hydrazine-isoporphyrin] -2'-yl) ethyl ketone hydrobromide 7 ΝΗ \ II: cut &gt; , -ο 1-(3-tert-butyl-4-decyloxy_ 5 _ 吓 · phenyl) _ 2 _ (5,,6'-diethoxy-3'-imido-spiro [ Cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide 17 95255 201242964 8 NH \ HBr 0 1-(3-tert-butyl-4-methoxy_5_ntb -1_yl-phenyl) _2_(5',6'-diethoxy-3'-imino-spiro[cyclopropan-1,1'-iso-°°°朵淋]-2' - Ethyl ketone hydrobromide 9 NH \ HBr 0 1-(3-tert-butyl-4-methoxy-5-morphinylphenyl)_2_(7-imino-2, 5-dimethyl -5-Phenyl-indole 11 each [3, 4-6] 0 is more than 6-yl) ethyl ketone oxime bromide 10 NH \ HBr ^ 1-(3, 5-di-tert-butyl-4 -Phenylphenyl)-2-(5',6'-diethoxy_3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethanone Hydrobromide 11 NH \ II: Sentence 7^. , HBr 1 -(3-tert-butyl-5-diethylamino-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[ Cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 12 NH \ II. Cut &quot;^. , HBr O 卜 [3-tert-butyl-4-methoxy-5-(1-pyranyl)phenyl]-2-(5',6'-diethoxy-3'-imino - snail [cyclopropane _1,1' _isoporphyrin]-2'-yl)ethanone hydrobromide 13 NH \ NH HBr 0=^ N-[3-tert-butyl-5-[2 -(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethenyl]-2-indolyloxy Phenyl]acetamide hydrobromide 18 95255 14 NH \ Χ〇ϊ^Ν&gt;^° NH HBr < CN 2-[[3-tert-butyl-5-[2-(5',6'_二Ethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-2-indolylphenyl]amino]acetonitrile hydrogen Bromate 15 NH \ N" HBr —/ 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzoxoxazin-6-yl)-2-( 5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone hydrobromide 16 NH \ HBr < CN 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-iso. bowbendene] -2'-yl)ethinyl]-2,3-diaza-1,4-benzoxazin-4-yl]acetonitrile hydrobromide 17 P HBr 〇 [3-(1-adamantyl)-4-methoxy_5-morphinyl phenyl]-2-(5',6'-diethoxy-3'-imido- snail [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide 18 NH \ N" HBr ( 〇V〇L 2-[8-tert-butyl-6-[2- (5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-2, dihydro- 1,4- benzoxazin-4-yl]ethyl acetate hydrobromide 19 95255 201242964 19 NH \ HBr /N 1-(8-tert-butyl 4-methyl-2,3-diindole-1 , 4-benzoxazine_6_yl)_2_(5',6' _diethoxy_3'-imino-spiro[cyclopropane-1,1'-isoindoline] -2' - Ethyl ketone hydrobromide 20 X sentence &gt; 4^°, H. 0 1-[3-(4-Ethylpiperazin-1-yl)-5-tert-butyl-4-decyloxy Phenyl]_2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide Salt 21 NH \ HBr / 1-1-(3, 5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imido-snail [Cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 22 HBr I ~ 1-(3, 5-Di-tert-butylphenyl) _2-(5',6' _diethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin] -2'-yl) ethyl ketone hydrobromide 23 NH \ HBr V ~ 1-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy _7'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole]_ 2 ' _yl) acetamidine hydrogenate salt 24 HBr V ~ 1-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2 -yl) ethyl ketone hydrobromide 20 95255 201242964

25 NH \ 1-(3-tert-butyl-4-methoxy-5-B Bihayuan-1-yl-phenyl)-2-(7-imino-2, 5-didecyl) 5_Phenyl_tr piroxi[3,4-/&gt;]pyridin-6-yl)ethanone hydrobromide 26 ηβγ 0 1-(3-tert-butyl-4-methoxy-5- ° ratio of 17 -1-yl-phenyl) -2-(5,6-diethoxy_4-carb-3-imino-1,1-didecyl-isoindole B-lin - 2-yl) ethyl ketone hydrobromide 27 f NH \ -0 1-(3-tert-butyl-4-oxooxy-5-morphinylphenyl)-2-(5,6-diethoxy_ 4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 28-Ο 1-[3-tert-butyl-4-decyloxy -5-(1-piperidinyl)phenyl]-2-(5,6-diethoxy-4-gas-3_imino-1,1-diindolylisoindoline-2- Ethyl ketone oxime bromide 29 χώ^-ν^ο HBr ο, ΝΗ N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-gas-3-imine) Base-1,1-dimercapto-isoindol-2-yl)ethinyl] _2-decyloxyphenyl]ethinamine hydrobromide 21 95255 201242964 30 χύχ-γ^0 HBr 1- (8-tert-Butyl-4-methyl-2,3-diazepine-1,4-abido.oxazin-6-yl)-2-(5,6-diethoxy-4-fluoro- 3-imino-1,1-diindole Iso-oxalin-2-yl)ethanone hydrobromide 31 2-[8-tert-butyl-6-[2-(5,6-diethoxy-4-dun-3-imine) Benzyl-1,1-dimethyl-isoindolin-2-yl)ethyl aryl]_2,3_dihydro-1,4-benzoindole-4-yl]ethyl acetate hydrobromide 32 P HBr 0 1-[3-(1-adamantyl)-4-decyloxy-5-morphinylphenyl]-2-(5,6-diethoxy-4-^-3-imine Base-1, Γ-dimethyl-isoindol-2-yl)ethanone hydrobromide 33 -〇〇:ixN&gt;4^ HBr —” 1-(8-tert-butyl-4-ethyl _2,3-diaza-1,4-benzo-oxazin-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-di Methyl-isoindolino-2-yl)ethanone hydrobromide 34 f NH \ HBr V-1-(3, 5-di-tert-butyl-4-decyloxyphenyl)-2-(5 ,6-diethoxy-4-fluoro-3-imino-M-dimercapto-isoindol-2-yl)ethanone hydrobromide 35 X〇i^N&gt;^ HBr / 1_(3,5-di-tert-butylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-didecyl-iso-p-alpha -2-yl)-ethanone hydrogen oxalate 22 95255 201242964

36 II: Department of poetry, ΗΒ "Ο l-[3-tert-butyl-4-methoxy-5-(1-° butyl) phenyl]-2-(5,6-diethoxy- 1,1-diethyl-4-say-3-imino-isoindol-2-yl)ethanone hydrobromide 37 two-phase j^., ηβγ 0 1-(3-tert-butyl -4-methoxyxanthene-1-yl-phenyl)-2-(5,6-diethoxy-1,1-diethyl-4-den-3-imido)朵多琳-2-yl) ethyl ketone hydrobromide 38 -0 1-(3-tert-butyl-4-methoxy_5_mlylphenyl)-2_(5,6-diethoxy_ 1,1-diethyl-4-fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide 39 h. H 1-[3-tert-butyl-4-oxo -5-[(1 550 550-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2-(5,6-diethoxy-4-fluoro -3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 40 f NH \ book % 1-[3-tert-butyl-4-methoxy -5-(2-oxa-6-azaspiro[3. 3]hex-6-yl)phenyl]-2_(5,6-diethoxy-4_gas-3_imino-1 ,1-dimercapto-iso-inducing π-system-2-yl)ethanone hydrobromide 23 95255 201242964 41 two-phase &gt;^., -0 1-(3-tert-butyl-4-oxo 5--5-morpholinylphenyl)-2 -(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl) ethyl ketone hydrobromide Salt 42 HBr /\ 1-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulina [cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 43 N-/ HBr ( &gt; 〇v_ 2-[8-tert-butyl-6-[2 -(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethyl] _2,3_Dinitro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 44 HBr / 1-(3, 5-di-tert-butylphenyl) _2-(5,, 6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 45 f NH \ HBr V ~ 1-(3, 5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imido group - snail [cyclopropanone-1,1'-isoindolin]-2'-yl)ethanone hydrobromide 24 95255 201242964

46 ηβγ 0 1-(3-tert-butyl-4-methoxy-5-° ratio p-sinter-1-yl-phenyl)-2-(5',6'-diethoxy-4' -fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 47 -0 1-[3-(1-adamantane ))-4-decyloxy-5-morphinylphenyl]_2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine -isoporphyrin]-2'-yl)ethanone hydrobromide 48 HBr 1-[3-[(1 especially 5«-3-azabicyclo[3. 1.]]-3-yl] _5_tert-butyl-4-decyloxyphenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime- Isoporphyrin]-2'-yl)ethanone hydrobromide 49 f NH \ N-^ HBr L 2 - [8-tert-butyl-6-[2-(5',6'-diethoxy -4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethidyl]-2,3-diaza-1,4- Benzoxazine-4-yl]acetonitrile hydrobromide 50 T NH \ II.1HBr ," 1-(8-tert-butyl-4-methyl_2,3-dinitro-1,4- stupid And oxazin-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoindole] -2 -yl)ethanone hydrobromide 25 95255 201242964 51 f NH \ -〇〇X^N&gt;4l ΗΒΓ _TJ 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4 -benzoxazin-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindene ]-2'-yl)ethanone hydrobromide 52 1-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]-2-(7-imido) -2,5-diindenyl_5_phenyl_ π ratio 11 and [3,4-/?]pyridine-6-yl)ethanone hydrobromide 53 f NH, two-phase w., -0 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)-b (4 -methoxy-3-?-_5-trimethylsulfanyl-phenyl) ethyl ketone hydrobromide 54-Ο 1-[3-tert-butyl-4-methoxy-5-U-peri Pyridyl)phenyl]anthracene, 6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1, Γ-isoindoline]-2'-yl) Ethylketone hydrobromide 55 HBr 1-[3-[(1 especially 5«-3_ azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-decyloxybenzene Base]_2-(5,diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2- ) Ethanone hydrobromide 2,695,255,201,242,964

56 NH \ Η 1-[3-[(1 foot 55*)-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl] _2_(5',6'-diethoxy_3'-imino-spiro[cyclopropan-1, Γ-isoindoline]-2'-yl)ethanone hydrobromide 57 f NH \ -0 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)-1-(4-methoxy基_3-么琳_5_三methyl梦-phenyl) ethyl ketone hydrobromide 58 NH \ 1-(3-tert-butyl-4-methoxy-5-吼11 each bright -1- -Phenyl)-2-(7-imino-2-indolyl-5-mercapto-5-phenylpyrrolo[3,4-/?]° ratio °-6-yl) Ethylketone hydrobromide 59 NH \ n HBr V-〇1-(3-tert-butyl-4-decyloxy-5-morphinylphenyl)_2_(7-imino-2-methoxy- 5-methyl-5-phenyl ratio p and [3, 4-Z?]D ratio bit-6-yl) ethyl ketone arborate 60 HBr 1-(3, 5-di-tert-butyl-4 -hydroxyphenyl)-2-(7-imino-2-indolyl-5-mercapto-5-phenyl-D ratio p and [3, 4-??]β ratio bite-6- Ethyl ketone hydrobromide 61 HBr ^~f 1-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]-2-(7-imino-2 -decyloxy-5-mercapto-5-phenyl-pyrrolo[3,4-Z?]° than pyridine-6-yl Ethyl ketone hydrobromide 27 95255 201242964 62 NH \ HBr , CN 2-[[3-tert-butyl-5-[2-(7-iminoamino-2-methoxy-5-methyl_ 5 _ Phenyl-咐σ each [3, 4-Ζ?] π ratio -6-yl) ethinyl]-2-methoxyphenyl]amino] acetonitrile hydrobromide 63 n HBr 1-( 3-tert-butyl-4-methoxy-5-morphinylphenyl)_2_(3-imino-1-methyl-1-phenylpyrazine[3, 4-Ζ?]°Ι:琳-2-yl) ethyl ketone hydrobromide 64 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(3-imino- 1-methyl-1-phenyl ratio ρ-[3,4-Z?]quinolin-2-yl)ethanone hydrobromide 65 NH \ H, Ν-[3-tert-butyl-5- [2-(7-Imino-2,5-diamidino-5-phenyl-σ ratio ρ[3, 4-/?]° pyridine-6-yl)ethinyl]-2 -decyloxyphenyl]acetamide hydrobromide 66 f NH v II: electricity &gt;^\ Ν'! HBr Q 1-[3-tert-butyl-4-decyloxy-5-(2- Oxa-6-azaspiro[3. 3]hex-6-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-snail [Cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 28 95255 67 Nx HBr (H l-[3-tert-butyl-4-decyloxy-5- [(l especially 550-8-oxa-3-aza) Ring [3.2. 1]oct-3-yl]phenyl]-2_(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1' -isoline]-2'-yl)ethanone hydrobromide 68 χώ^^°0 〇HBr 0_y 1-[3-tert-butyl-4-decyloxy-5-(?琳-4- Phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide Acid salt 69 xiiA HBr 1 -[3-tert-butyl_5-(1-yl-1-yl-yl)ethyl]-2-(5,6-diethoxy_4-d- 3_imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 70 χάί^〇Η HBr 1-[3-tert-butyl-5-(1-trans-based _1-mercapto-ethyl)phenyl]- 2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorene-isoindole Porphyrin]-2'-yl)ethanone hydrobromide 71 χάί&gt;^ HBr V-0 1_[3-(4_Ethyl π- bottom σ-qin-1-yl)-5-tert-butyl-4 -decyloxy-phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethanone hydrobromide 29 95255 201242964 72 HBr ^-N 1_ [ 3-(4-ethyl-branched B-methyl-1-yl)-5-tert-butyl 4-methoxyl-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Ethyl ketone hydrobromide 73 1 HCI HO 3_tert-butyl _5_[2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole淋-2-yl)ethinyl]benzoate hydrochloride 74 / y-N HC, w 1 - [3_tert-butyl-5-(m-lin-4-carbonyl)phenyl]-2-(5 ,6-diethoxy-4-^-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrochloride 75 f NH 0 /=(^ χΛ^ ^Ηο 1 &gt;-K HCI 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-di Mercapto-isoindoline-2-yl)ethenyl]benzamide hydrochloride 76 f ,NH 0,/=&lt;X q HO HCI 3-tert-butyl-5-[2-(5 ',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]benzoic acid Hydrochloride 77 / HBr 2-[[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-iso) Porphyrin-2-yl)ethinyl]phenyl]amino]acetonitrile hydrobromide 30 95255 201242964

78 N-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro_3'-imino-spiro[cyclopropyl]-1,1'- Isoporphyrin]-2'-yl)ethinyl]phenyl]acetamidine hydrobromide 79 N-[3-tert-butyl-5-[2-(5,6-diethoxy- 4-oxa-3-imino-1,1-didecyliso-α-lead _ 2 -yl)ethyl phenyl] phenyl] acetamide hydrobromide 80 \ HN HBr V 3- un Butyl-indole-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl Ethyl)-2-methoxy-benzamide hydrobromide 81 ^ HN HBr V 3-tert-butyl-fluorene-cyclopropyldiethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethylidene]-2-decyloxy-benzoguanamine hydrobromide 82 f , NH 0, f= C^ χά^4. 1 HN HCI H0_^ HO 3_tert-butyl_5_[2_(5,6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-isoindoline-2- Ethyl)-hydrazino]-(2,3-dihydroxypropyl)phenylhydrazine hydrochloride 83 f , NH 0, /= (XZ HN HCI \&gt; 3-tert-butyl-fluorene-ring Propyldiethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-U'-isoindoline]-2'-yl)ethinyl]benzamideamine hydrochloride 31 95255 201242964 84 f NH 0, /=(^ HCI ^_) l-[3-tert-butyl-5-(morphin-4-yl)phenyl]-2-(5',6'-di Oxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-ethyl ketone hydrochloride 85 『NH 0, /=(^ χΛ/ ^ο 丨H 乂HCI HO" 3_tert-butyl-5_[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoporphyrin) -2-yl)ethinyl]-N-(2-hydroxyethyl)phenylhydrazine hydrochloride 86 2-[[3-tert-butyl-5-[2-(5',6'-II Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenyl]amino] acetonitrile hydrobromide Acid salt 87 f NH /=\ ^0yVn&gt;Q )=〇HC,H0-) 3-tert-butyl-5-[2-(5, 6-diethoxy-4- Fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl)ethenyl]-N,N-bis(2-hydroxyethyl)benzoguanamine hydrochloride 88 Xi^. z HN HCI H〇V_^ OH 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, 1'-Isoporphyrin]-2'-yl)ethinyl]-N-(2,3-dipropylpropyl)benzoguanamine hydrochloride 32 95255 201242964 89 χώίΗ ζ ΗΝ HC丨^ ΟΗ 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1,1'-isoporphyrin) ]-2'-yl)ethinyl]-2-ylpropyl)benzamideamine 90^ ΝΗHBr 1-[3-tert-butyl-5-(2-hydroxyethoxy) Phenyl]_2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorene-isoindoline]-2'-yl) Ketone hydrobromide 91 f ΝΗ 0 /7-1 HBr&gt; 1 _(3_tert-butyl_5_methylgendrexate-phenyl)-2-(5,6-diethoxy-4-ya Amino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 92 1-(3-tert-butyl-5-methylsulfonyl-phenyl)_2_(5' ,6'-diethoxy_4'-gas-3'-imino-spiro[cyclopropan-1,1'-iso-induction 0-lin]-2'-yl)ethanone hydrobromic acid Salt 93 Χώ{νχ〇Η HB, ^ 1_[3_tert-butyl_5_ (2,3-di-dipropylpropoxy)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine -isophthalene]-2'-yl)ethanone oxime bromide 94 f NH 0 /ri ^ HBr 3-tert-butyl_5-[2-(5, 6-diethoxy-4-fluoro -3-imino-1,1-dimercapto-isoindol-2-yl)ethyl phenyl benzoate hydrobromide 33 95255 201242964 95 y ηβγ 3_tert-butyl_5_[2_ (5',6' _diethoxy_4'-fluoro^-3' _imino-spiro[cyclopropan-1,1'-isoindoline]-2'-yl)ethenyl Benzoonitrile hydrobromide 96 OH HBr 1-[3-tert-butyl-5-(hydroxyindenyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro- 3'-Imino-spiro[cyclopropane-1, hydrazine-isoindole]-2'-yl)ethanone hydrobromide 97 HBr 1-[3-tert-butyl-5-(2- Ethyloxy)phenyl]_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone oxime bromate Salt 98 HBr l〇H 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5,6-diethoxy-4-fluoroimino-1, 1-di Mercapto-isoindolino-2-yl)ethanone hydrobromide 99 ..» N HBr | 1-[3-un Butyl-5-(polymethyl-pyran-4-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-iso吲哚琳-2-yl) ethyl ketone hydrobromide 100 f NH 0, λ-/ HBr, n'n 1 1-[3-tert-butyl-5-(1-mercaptopurine 嗤-4- Phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-iso-σ-D Dulin]-2 '-yl) ethyl ketone arborate 34 95255 101 f NH 0 /r~C^ HBr 1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5, 6-diethyl Oxy_4-gas-3-imino-1,1-didecyl-iso- 0-dot-dot-_2-yl)ethanone argon bromide 102 ί NH 0, λ-Χώέ崎^ HBr / 1-(3-tert-butyl-5-isopropyl-phenyl)_2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 ,1'-isoporphyrin]-2'-yl)ethanone hydrobromide 103 〇HBr ^^ OH 1-[3-tert-butyl-5-[4-(2-hydroxyethyl) pie 11 Qin_1_yl]phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorene-isoporphyrin] -2'-yl) ethyl ketone hydrobromide 104 Χώί&gt;&lt;HBr 1-(3-tert-butyl-5-cyclopropyl-phenyl)-2-(5' 6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone hydrobromide 105 f NH 0 /j-1 HBr ^ 1-(3-tert-butyl-5-cyclopropyl-phenyl)_2-(5,6-diethoxy-4-fluoro-3-imino-1,1- Dimercapto-isoindolino-2-yl)ethanone hydrobromide 106 ί NH 0 η—ί 1-[ 3-tert-butyl-5-(trifluoromethyl)-phenyl]_2_(5 ,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 35 95255 201242964 107 /J ^ HBr FF 1-[3-tert-butyl-5-(trimethylsulfonyl)-phenyl]_2~(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ring] Propionate-1,1'-isoindolin-2'-yl)ethanone hydrobromide 108 f NH v HBr 2-[3-tert-butyl-5-[2-(5',6' -diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethidyl]phenyl]-2-indenyl -propionitrile hydrobromide 109 f NH \ ΗΒΓ Know 2-[3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1 -dimercapto-isoindole D-dolin-2-yl)ethinyl]phenyl]-2-methyl-propionitrile hydrobromide 110 H CI OH 3-tert-butyl_5-[2-(5',6'-diethoxy_4'-don-3'-imino-spiro[cyclopropane-1,1'-isoindole] Porphyrin]-2'-yl)ethinyl]-N,N-bis(2-hydroxyethyl)phenylhydrazine hydrochloride 111 Χώί&gt;&lt;Κ ^ HCI 0 H 3-tert-butyl-5- [2-(5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, oxime-iso.弓布朵惊]]-2'-yl) ethyl aryl]-N-[2-carbyl-1-(transylhydrazino)ethyl]phenyl hydrazine hydrochloride 36 95255 201242964 112 〇HBr ^ ^ OH l-[3-tert-Butyl-5-[4-(2-hydroxyethyl) 嗓-1-yl]phenyl]_2-(5,6-diethoxy-4-fluoro-3 -imino-1,1-dimethyl-isoindolin-2-yl)ethanone argon bromide 113 f NH 0 r.~\ ^°rVN&gt;^ 〇S)OH HBr (0H 1_ [3_tert-Butyl-5-(1,2-dihydroxyethyl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone argon bromide 114 f NH \ Ο -〇^N> 〇H HBr ' 2-[3-tert-butyl-5 -[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetic acid Phenyl]-2-yl-propionic acid hydrobromide 115 f NH \ ΗΒΓ ^〇H 1-[3-tert-butyl-5-(2-hydroxy-1,1-didecyl-B Phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropene _1,1' _iso°°°朵琳] _2'-yl) acetamidine compound 116 1-(4_tert-butyl-lH-ntb11 each_2_yl)-2-(5 ,6' _diethoxy-4'-fluoro-3'-imino-spiro [cyclopropene-1, Γ-iso-sigma π-linlin] -2'-yl) ethyl ketone hydrobromide 117 f NH 〇, 1-(2, 6-di-tert-butyl-4-pyridine)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl Iso-oxalin-2-yl)ethanone hydrobromide 37 95255 201242964 118 HBr / ~ 1-(2,6-di-tert-butyl-4-0-pyridyl)-2-(5',6 '-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone hydrobromide 119 八HBr 1- (3-tert-Butylpyrrol-1-yl)-2-(5,6-diethoxy_4-fluoro-3-imino-1,1-dimercapto-isoindoline-2- Ethyl ketone hydrobromide 120 χώί&gt;^ 1-(3-tert-butylpyrrol-1-yl)-2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide salts Typical compounds of the invention also include, but are not limited to: Compound No. Structure Name 1, NH \ 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'- Isoporphyrin] -2' -yl)ethanone 2,NH \ 0 1-(3-tert-butyl-4-methoxy_5_? 吓 phenyl)_2-(3 _imino-5',6'-dioxin Oxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone 38 95255 201242964

3, 1-(3-tert-Butyl-4-decyloxyphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ- Isoporphyrin]-2'-yl)ethanone 4, ΝΗ \ :〇^ν&gt;Φη Βγ 1-(3-Mo-5-tert-butyl-4-ylphenyl)-2-(3) Amino-5',6'-dimethoxyoxyspiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethanone 5, ΝΗ \ Ν_/ κ_ 0 Ν— 2-[8- tert-Butyl-6-[2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1, Γ-isoindole]-2')) Brewed base] _2,3-diaza-1,4-benzoxoxazin-4-yl]acetate 6 , ΝΗ ν :〇^Ν&gt;4ΐ 1-(8-tert-butyl-4-ethyl _2,3-diaza-1,4-benzoxoxazin-6-yl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1 ,1'-isoindolin]-2'-yl)ethanone 7, ΝΗ \ 0 1-(3-tert-butyl-4-decyloxy-5-morphinylphenyl)_2-(5', 6'-Diethoxy-3'-imino-spiro[cyclopropane-1, Γ-isoindole] - 2'-yl) ethyl ketone 8, ΝΗ \ 0 1-(3-tert-butyl 4-methoxy-5-°pyrrolid-1-yl-phenyl)-2-(5',6'-diethoxy-3 -imino-spiro[cyclopropane-1, oxime-isoindolin]-2'-yl)ethanone 39 95255 201242964 9, NH \ 0 0 1-(3-tert-butyl-4-methoxy _5_?lin phenyl)_2-(7-imino-2,5-dimethyl-5-phenyl-D ratio p and [3, 4-Ζ?]α is more than 唆-6-yl Ethylketone 10' NH \ 1-(3, 5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[ring] Propane-1, hydrazine-isoporphyrin]-2'-yl)ethanone 11, NH \ o 1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)-2 -(5,,6'-diethoxy-3'-imino-spiro[cyclopropanone_1, 1' _isoindole]-2'-yl)ethanone 12' NH \ o 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(5',6'-diethoxy-3'-imino-snail [Cyclopropanone-1,1 ' _isoline]-2'-yl)ethanone 13, NH \ NH 0夂N-[3-tert-butyl-5-[2-(5',6' -diethoxy-3'-imino-spiro[cyclopropanone_1,1' _isoporphyrin]-2'-yl)ethenyl]-2-nonyloxyphenyl]acetamidine Amine 14, NH \ two pairs &gt; \ NH &lt;〇N 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, Γ-iso)吲°朵琳]-2'-yl)ethinyl]-2-methoxyphenyl]amino]acetonitrile 40 95255 201242964 15' NH \ 1-(8-tert-butyl-4_ethyl-2 ,3-dihydro-1,4-benzo-oxazine-6-yl)-2-(5',6'-diethoxy-3'-imido-spiro[cyclopropane-1, hydrazine - 异吲哚琳]-2' _ base) acetamidine 16, NH \ N-/ L 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3' -imino-spiro[cyclopropan-1,1'-isoindoline]-2'-yl)ethenyl]-2,3-dihydro-1,4-benzoxazine-4- Acetonitrile 17, P 0 1-[3-(1-adamantyl)-4-methoxy-5-l-phenyl]-2-(5',6'-diethoxy-3' -imino-spiro[cyclopropene*_ 1,1 '~iso- 0 lead D-line]-2'-yl)ethanone 18' NH \ y°^- 2-[8-tert-butyl-6 -[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropanone-1,1 '-iso 11 π 朵 淋]-2'-yl)acetate group] -2, Dihydro-1,4-benzoxazin-4-yl]acetate 19, NH \ Γ 1-(8-tert-butyl 4-indolyl-2,3_digas-1,4 _Benzene恶oxazin-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl) Ethyl ketone 41 95255 201242964 20, 0 l_[3-(4-Ethyl α 嗓 嗓-1-yl)-5-tert-butyl-4-decyloxyphenyl]-2-(5',6' -diethoxy_3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone 21, 1-(3,5-di-tert-butyl-4 -nonyloxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, Γ-iso-indolyl]-2'-yl) Ketone 22' NH \ 1-(3, 5-di-tert-butylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, oxime- Isoporphyrin]-2'-yl)ethanone 23, 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-7' -fluoro-3'-imino-spiro[cyclopropane-1, fluorene-isoindolyl]-2'-yl)ethanone 24' 1-(3,5-di-tert-butyl-4-hydroxybenzene 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone 25, NH \ 1- (3-tert-Butyl-4-methoxy-5-^bp each 1-yl-phenyl)-2-(7-imino-2, 5-difluorene) _5_ _σ Bulow and phenyl [3, 4- /?] Pyridin-6-yl) ethanone 4,295,255,201,242,964

26, 0 1-(3-tert-butyl-4-methoxy_5_β than oxime-1_yl-phenyl) _2-(5,6-diethoxy-4-dun-3-imine 1,1-dimethyl-isoindol-2-yl)ethanone 27, 0 1-(3-tert-butyl-4-oxooxy-5-morphine phenyl)_2-(5 ,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone 28, ο 1-[3-tert-butyl-4-曱oxy-5-(1-piperidinyl)phenyl]-2-(5,6-diethyl _4_milo-3_imino-1,1-dimethyl&quot; Lin-2-yl)ethanone 29, ΝΗ N-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3_imino-1,1_diindole) Base-iso 11 π 琳 琳 -2- 基 基 醯 ] ] ] ] ] ] γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ 2,3_Dinitro-1,4-benzo-3-oxazin-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl Ethyl-isoindolin-2-yl)ethanone 31, χύχ-γ^ W" Sr, ο Ν 2- [8-tert-butyl-6-[2-(5, 6-diethoxy- 4-Qi_3_imino-1,1-dimethyl-iso-dec. Dolin-2-(yl)acetate]-2,3-dihydro-1,4-benzoxazine-4- Ethyl acetate ethyl acetate 43 95255 201242964 32 , 0 1-[3-〇-adamantyl)-4-decyloxy-5-morphinyl]-2-(5,6-diethoxy-4-fluoroi-3-imido -1,1'-dimethyl-isoindol-2-yl)ethanone 33, "H" 1_(8-tert-butyl-4-ethyl-2,3-dihydro-1,4- Benzo-oxazin-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-didecyl-iso-α-inducing π-scarring--2 -yl)ethanone 34, 1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino- 1,1-dimercapto-isoindol-2-yl)ethanone 35, Χ〇:άχΝ&gt;^ 1-(3,5-di-tert-butylphenyl)-2-(5,6-di Ethoxy-4-fluoro-3-imino-1,1-dimethyl-iso-D-[Delta]2-yl)-acetamidine with 36, ο 1-[3-tert-butyl-4- Methoxy _5-(1-pyranyl)phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-imino-iso-anion朵多惊*-2-yl) Ethylketone 37' 0 1-(3-tert-butyl-4-methoxy-5-°pyrrol-1-yl-phenyl)-2-(5,6 -diethoxy-1,1-diethyl- 4-fluoro-3-imino-isoindole-2-yl)ethanone 44 95255 201242964

38' 0 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-1,I-diethyl-4-fluoro- 3-imino-isoindolin-2-yl)ethanone 39, f NH \ Θ- H 1-[3-tert-butyl-4-methoxy-5-[(1 brother 550-8- Oxa-3-azabicyclo[3·2. 1]oct-3-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1 -dimercapto-isoindoline-2-yl)ethanone 40, f NH \ % 1-[3-tert-butyl-4-methoxy-5-(2-oxa-6-aza snail [3. 3]hex-6-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline- 2-yl)ethanone 41, HBr 〇1-(3-tert-butyl-4-decyloxy-5-n-butylphenyl)-2 -(5',6'-diethoxy-4'- Fluoro-3'-imino-spiro[cyclopropane_1,1'-isoindoline]-2'-yl)ethanone 42,f NH \ 1-(3, 5-di-tert-butyl-4 -hydroxyphenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindolin-2] -yl)ethanone 45 95255 201242964 43, N-/ 0 N-2- [8_ tert-butyl_6_[2-(5',6'-diethoxy-4'-fluoro-3'-imine Base-spiro [cyclopropane-1,1'-iso Porphyrin]-2'-yl)ethylidene]-2,3-dinitro-1,4-benzoxazin-4-yl]ethyl acetate 44, 1-(3, 5-di-tert-butyl Phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl) Ethylketone 45' f NH \ 1_(3, 5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy_4'-fluoro*-3' - Imino-spiro[cyclopropane-1,1'-isoindolyl]-2'-yl)ethanone 46, 0 1-(3-tert-butyl-4-methoxy-5-β ratio 11 Each of 1-yl-phenyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole Porphyrin]-2'-yl)ethanone 47, 0 1-[3-(1-adamantyl)-4-decyloxy-5-morpholinylphenyl]-2-(5,,6' _ Ethoxy-4'-I _3'-imino-spiro[cyclopropyl-1-, Γ-isoporphyrin]-2'-yl)ethanone 46 95255 48, f NH \ 卜 [3-[ (iy?,5«-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-decyloxyphenyl]_2-(5',6'-di Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone 49, c 2-[8_ tert-Butyl-6_[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropene-1, hydrazine-isoindoline]-2' -yl)diyl]_2,3~diazo-1,4-benzoxazin-4-yl]acetonitrile 50, f NH \ / 1-(8-tert-butyl-4-fluorenyl-2, 3-dihydro-1,4*~benzothiazin-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ring丙烧-1,1'-iso σ引π朵琳]-2'-yl) acetamidine 51, f NH V -〇〇X^N&gt;^ _/ 1-(8-tert-butyl-4-B Base-2,3-dihydro-1,4-benzo-11oxazin-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulina [cyclopropane-1,1'-iso-peptone]-2'-yl)ethanone 52, 1-[3_tert-butyl-4-decyloxy-5-(1-piperidinyl) Phenyl]-2-(7-imino-2,5-diindenyl-5-phenyl-π-pyrolo[3,4-Z?] 0 is more than -6-yl) B-7 95255 201242964 53, 0 2-(5',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl )-1-(4-decyloxy-3-morphinyl_5_tridecylpyridyl-phenyl)ethanone 54'f ΝΗ \ : phase &gt; \ Ο 1-[3-tert-Butyl-4-methoxy-5-(abridinyl)phenyl]anthracene, 6'-diethoxy-4'-fluoro-3'-imido - spiro [cyclopropane-1,1'-isoporphyrin]-2'-yl)ethanone 55, bifurcated [3-[(1/?,5«-3-azabicyclo[3. 1 .0]Hex-3-yl]-5-tert-butyl-4-decyloxyphenyl]_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-di Mercapto-isoindoline-2-yl)ethanone 56, ΝΗ ν 2:pair &gt;^\ Η 1_[3-[(1疋5^)-3-azabicyclo[3. 1. 0] Hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'-imido-spiro[cyclopropane-1, Γ-Isoporphyrin]-2'-yl)ethanone 57, f ΝΗ , χώ/&gt;φχ 0 2-(5,6-diethoxy_4-carb-3-imino-1, 1-Dimercapto-isoindoline-2-yl)-1-(4-methoxy-3-triazep-5-trimethylsulfonium-phenyl)ethanone 48 95255 58' NH \ n 1-(3-tert-butyl-4-decyloxy-5_npyroxy-1_yl-phenyl)-2-(7-iminoamino-2-oxo-5-indenyl-5- Phenyl ratio 11 and [3,4-Z?]0 ratio bite-6_yl) acetamidine 59 NH \ Hi 1-(3-tert-butyl-4-decyloxy- 5_? _2_(7_imino-2-oxo-oxygen 5-5-methyl-5-phenyl-n ratio σ[3,4-Z?]pyridine-6-yl)ethanone 60, 1-(3,5-di-tert-butyl-4-hydroxybenzene Benzyl-2-(7-imino-2-yloxy-5-fluorenyl-5-phenyl-πpyrho[3,4_Ζ?]π π-6-yl)ethanone 61, NH \ n 1-[3-tert-butyl-4-methoxy-5-(1-piperidinyl)phenyl]-2-(7-iminoamino-2-oxo-5-indenyl) - 5-Phenylpyrolo[3,4-anthracenepyridin-6-yl)ethanone 62, NH \ n CN 2-[[3-tert-butyl-5-[2-(7-imino) -2-decyloxy-5-methyl-5-phenylpyrolo[3,4-indolyl]pyridin-6-yl)ethenyl]-2-indolylphenyl]amino]acetonitrile 63' CC^ 1-(3-tert-butyl-4-decyloxy-5-morpholinylphenyl)-2-(3-imino-1-indolyl-1-phenyl-. [3,4-«Quinolin-2-yl)ethanone 49 95255 201242964 64, n 1-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]-2 -(3-imino-I-fluorenyl-1-phenyl ratio p-[3,4-Z?]indol-2-yl)ethanone 65, NH v N-[3-tert-butyl -5-[2-(7-imino-2,5-didecyl-5-phenyl-11-pyrolo[3,4_Z?]indolepyridin-6-yl)ethenyl]-2-曱oxyphenyl]acetamide 66, f NH \ % 1-[3-tert-butyl-4-oxo 5-(2-oxa-6-azaspiro[3. 3]hex-6-yl)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3 '-Imino-spiro[cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone 67, f NH \ II: know &gt; , Nx 0'Ή Η 1-[3-tert-butyl-4-methoxy-5-[(1 brother 5«-8-oxa-3-azabicyclo[3.2.1]oct-3-yl Phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-iso D bow 丨°朵琳]- 2'-yl)ethanone 68, 0 1-[3-tert-butyl-4-methoxy-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy 4-fluoro-3-imino-1,1-didecyl-isoindol-2-yl)ethanone 69, xt^A 1-[3-tert-butyl-5-(1-hydroxyl -1-mercapto-ethyl)phenyl]-2-(5,6-diethoxy_4_gas_3_imino-1,1-didecyl-iso-inducing D-line-2 -基)乙嗣50 95255 70' ΧώίΑ Bu [3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]-2-(5',6'-diethoxy -4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone 71, y 卜 [3-(4-ethenyl) Pyrazin-1-yl)-5-tert-butyl-4-methoxy-phenyl]-2_(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone 72, y 1-[3-(4-ethinylpiperazin-1-yl)-5-tert-butyl-4-曱oxy-phenyl]-2-(5,6-di Oxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl) E-flavor I 73' ^ ΝΗ 0 /=(Χ Χώ^-^Ηο 丨ΗΟ 3 _tert-butyl_5_[2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethenyl]benzene Tannic acid 74, f ΝΗ 0 /==\ Χώ^-^ο 0 1_[3_tert-butyl_5-(Merline_4-re)phenyl]-2-(5,6-diethoxy 4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone 75, f, ΝΗ 0, /=(^ Χώ^-^%0 1 κ 3-tert-butyl-N-cyclopropyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-isoporphyrin -2-yl)ethinyl]benzamide 51 95255 201242964 76, f , ΝΗ 0, /==(^ ^ ΗΟ 3_tert-butyl_5_[2_(5',6' _diethoxy _4'-Dun-3'-imino-spiro[cyclopropane-1, fluorene-isoporphyrin]-2'-yl)ethenyl]benzoic acid 77, 2-[[3-tertidine _5-[2-(5,6-Diethoxyl-4-fluoro-3_imino-1,1-diindenyl-iso-α-inducing _ 2 _yl) ethyl benzene] benzene Acetyl]acetonitrile 78, Ν-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane] -1, 1'-Isoporphyrin]-2'-yl)ethinyl]phenyl]acetamidamine 79' Ν-[3-tert-butyl-5-[2-(5,6-diethoxy- 4-fluoro-3_imino-1,1-dimethyl-isoindolin-2-yl)ethinyl]phenyl]acetamido 80' 'ΗΝ V 3-tert-butyl-fluorene-ring Propyl-5-[2-(5,6-diethoxy_4-oxa-3-imino-1,1-didecyl-isoindoline-2-yl)ethenyl]- 2-decyloxy-benzamide 91, ^ ΗΝ 3-tert-butyl-fluorene-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3' -Imino-spiro[cyclopropane-1,1'-isoindolyl]_2'-yl)ethidyl]_2_decyloxy-benzoguanamine 52 95255 201242964 82' f ,ΝΗ 0 /=( ^ 1 ΗΝ ΗΟ-^ ΗΟ 3_tert-butyl_5_[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-isoindoline- 2-yl)ethinyl]-indole-(2,3-dihydroxypropyl)benzamide 83, χώίΗ Ζ ΗΝ V 3-tert-butyl-fluorene-cyclopropyl-5-[2-(5 ',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin]-2'-yl)ethenyl]benzamide 84' f ΝΗ 0, Χώ^-^ο 0 1-[3_tert-butyl_5_(吗吓·_4- 叛基)benzene ]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-ethyl ketone 85 , 丨ΗΝ Hoj 3_tert-butyl_5~[2_(5,6-diethoxy_4_gas-3-imino-1,1-dimercapto-isoindoline-2-yl Ethyl hydrazide]-Ν-(2-hydroxyethyl)phenyl hydrazine 86, J ^ Η CN 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy -4'-Fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethinyl]phenyl]amino]acetonitrile 87' γ ΝΗ 0 /=\ ^°yVn-&gt;0 ΗΟ-^^ &gt;=0 ΗΟ-^ 3_tert-butyl_5_[2_(5,6-diethoxy-4-fluoro-3-imino- 1,1-didecyl-isoindolin-2-yl)ethinyl]-indole, fluorenyl-bis(2-hydroxyethyl)benzamide 53 95255 201242964 88, z hn hcQ OH 3- un Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2' -yl)ethinyl]-N-(2,3-dihydroxypropyl)benzoguanamine 89, z HN 乂OH 3-tert-butyl-5-[2-(5',6'-di-B Oxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)acetamidine ]]-N-(2-hydroxypropyl)benzamide 90, 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]_2-(5',6'-di Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone 91, 1-(3-tert-butyl-5 -Methanesulfonyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-didecyl-isoindoline-2-yl) Ketone 92, 1-(3-tert-butyl-5-fluorenyl-phenyl)-2-(5',6'-diethoxy-4'-fluoro-3'-imido-snail [cyclopropane-1,1'-iso-phetidine]-2'-yl)ethanone 93, Χώί^°χ〇Η 1-[3_tert-butyl_5_(2,3_di-based Propoxy)phenyl]_2_(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1, Γ-iso-α αα朵琳]- 2'-yl)ethanone 54 95255 201242964

94, 3_tert-butyl_5-[2-(5,6-diethoxy_4-carb-3-imino-1,1-dimercapto-isoindoline-2-yl) Ethyl benzoate 95, 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3' _imino- snail [cyclopropanone _ 1,1'-isoporphyrin]-2'-yl)ethinyl]benzonitrile 96, f ΝΗ \ ^ΟΗ 1-[3_tert-butyl_5-(radiomethyl)phenyl] -2-(5',6'-diethoxy_4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone 97' 1-[3-tert-Butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1 -dimercapto-isoindoline-2-yl)ethanone 98, f ΝΗ \ / Υ~0Η 1-[3-tert-butyl-5-(hydroxymethyl)phenyl]-2-(5, 6-Diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone 99, Ν 1 1-[3-tert-butyl-5 -(1-indolyl π-p--4-yl)phenyl]-2-(5,6-diethoxy_4_qi_3_imino-1,1-didecyl-iso-introduction D-Dolin-2-yl) Ethylketone 55 95255 201242964 100, f NH 0, /rl 4 N 1 l-[3-tert-butyl-5-(1-methyloxazol-4-yl)phenyl ]-2-( 5',6'-diethoxy-4'-fluoro_3'-imino-spiro[cyclopropan-1,1'-iso-bambolin]-2'-yl)ethanone 101 ' f NH 0 /J-C^ 1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino- 1,1-dimercapto-isoindol-2-yl)ethanone 102' 1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5',6'-di Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindole]-2'-yl)B-103' 0 1-[3-tert-butyl -5-[4-(2-P-ethylethyl) 嗓-1-yl]phenyl]_2-(5',6'-diethoxy-4'-fluoro-3'-imino- Spirulina [cyclopropane-1, fluorene-isoindole]-2'-yl)ethanone 104' ί NH 0 /rl 1-(3-tert-butyl-5-cyclopropyl-phenyl)-2- (5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone 105, f NH 0 r.~/ 1-(3-tert-butyl-5-cyclopropyl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1- Dimethyl-isoindoline-2-yl)acetamidine with 56 95255 201242964 106' f NH 0 l-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2-(5, 6- Ethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone 107' 1-[ 3-tert-butyl-5-(trifluoroanthracene -phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-iso-inducing D-line] -2'-yl)acetamidine 108, J^-CN 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imine Base-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenyl]_2-methyl-propanenitrile 109, ^Λ-cn 2-[3_tert-butyl -5-[2-(5,6-diethoxy_4_gas_3_imino-1,1-diindolyl-isoindol-2-yl)ethenyl]phenyl]- 2-mercapto-propanoid 110' OH 3-tert-butyl-5-[2-(5',6' _diethoxy_4'-fluoro-3'-imino-spiro[cyclopropyl] _1,1'-isoporphyrin]-2'-yl)ethenyl]-indole, fluorenyl-bis(2-hydroxyethyl)benzamide 111' f NH 〇v /r~i OH 3 -tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1,1'-isoporphyrin] -2'-yl)ethinyl]-indole-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide 57 95255 201242964 112, 0 卜 [3-叔5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1 -Dimethyl-isoindoline-2-yl)ethyl hydrazine 113, f, NH 0, /7-/ ^ °^/S /0H OH 1_[3_tert-butyl_5-(1,2- Di-ethylidene)phenyl]-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin ]-2'-yl)ethanone 114' f NH \ 0 2_[3_tert-butyl_5_[2_(5',6'-diethoxy-4'-fluoro-3'-imido-snail [cyclopropan-1,1'-isoporphyrin]-2'-yl)ethenyl]phenyl 曱-2-mercapto-propionic acid 115, f NH v ~, 〇H 1-[3- tert-Butyl-5-(2-yl-1,1-didecyl-ethyl)phenyl]_2-(5',6'-diethoxy-4'-fluoro-3'-imine Base-spiro [cyclopropane-1, fluorene-isoindolyl]-2'-yl) acetam 116, 1-(4-tert-butyl-1H-pyrrole-2-yl)-2-(5', 6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoindoline]-2'-yl)ethanone 117, 1_(2,6- Di-tert-butyl-4_11 ratio -2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl) Ketone 58 95255 201242964 118' 1-(2,6-di-tert-butyl_4-σpyridinyl)-2-(5',6'-diethoxy-fluoro-3'-imido-snail [cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethanone 119' X-resin-1-(3-tert-butylpyrrole-1_yl)-2-(5,6-diethoxy 4- 4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethyl 120' 1-(3-tert-butylpyran-1-yl)-2 -(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1,1 '-iso-α丨丨π多琳]_2-yl) ----- or its pharmaceutically acceptable salt. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is present in a free or pharmaceutically acceptable acid addition form, the pharmaceutically acceptable acid addition salt Including hydrochloride, hydrobromide, methanesulfonate, sulfate, phosphate, maleate, malate, pulverized acid, acetate or trifluoroacetate, preferably hydrobromic acid Salt and hydrochloride. The present invention relates to a method for synthesizing a compound of the formula (I), which comprises: a compound of the formula (IA) or a compound of (IB)

201242964 reacts with a compound of the formula (IC) to give a compound of the formula (i);

(1C) wherein: X is selected from halogen, preferably a gas atom or a bromine atom; wherein: L'Y'R1 to R11 are as defined in the compound of formula (I), and the invention relates to formula (IA) or The compound shown in IB) is prepared as an intermediate of the compound of the formula (I),

Wherein: Y is selected from -CR12- or N atom; R, R2 and R3 are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an aryl nitro group, an alkoxy group, a decyl group, a banyl group, a block group, a cycloalkyl group, Heterocyclic group, aryl group, heteroaryl group, -C(0)0R15, -〇c(〇)R15, -〇(CH2)nC(〇)〇R15, -(CH〇nC(0)0R15, -C (0) R15, -NHC(0)R15, -S(〇)PR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 or _S(0)0NR16R17, wherein the alkoxy group is burned The base, the secret group, the transyl group, the silk or the heteroaryl group are further selected from one or more selected from the group consisting of i, perylene, cyano, hetero, alkoxy, leuco, cycloalkyl, heterocyclic, Aryl, heteroaryl, c(〇)〇Rl5, _〇c(〇)Rl5, -0(CH2)nC(0)0R15, -(CH〇nC(0)0R15,~c(〇)Rl5 , _NHC(〇)Rl5, 95255 60 201242964 _s(0)pRl5, —NR16R17, _〇c(〇)nr16r17 or -c(〇)nr16r17 substituted; &amp; R1 and R2 or R2 and R3 and phase The attached carbon atoms together form an aryl group, wherein the aryl group is further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, as desired. , Aryl, -C(0)0R15, -0C(0)R15, _〇(CH2)nC(〇)〇Rl5, _(CH2)nC(0)0Rl5, -C(0)R15, -NHC(0 a substituent of R15, -S(0)pR15, -NR16R17, -0C(0)NR16R17, -c(0)NR16R17 or -S(0)0NR16R17; R and R are each independently selected from cyano An alkoxy group, a pyridyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further required as needed One or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, _c(〇)〇Ri5, -〇C(0)R15,-0(CH2)nC(0) 0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(0)pR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 φ Or a substituent of -S(0)0NR16Rn is substituted; or, R4 and R5 together with the carbon atom to which they are bonded form a cycloalkyl group, wherein the cycloalkyl group is further selected from one or more selected from the group consisting of halogen, hydroxyl, and nitrate Substituted by a substituent of a cyano group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group or -NR16r17; R6 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, Heteroaryl, -C( 〇R15, -C(0)R15 or -c(〇)NR16R17, wherein the alkyl group, alkoxy group, cyclohexyl group, aryl group or heteroaryl group is further selected from one or more selected from the group consisting of halogen and hydroxyl groups, as needed , nitro, cyano, alkyl, alkoxy, cycloalkyl 61 95255 201242964 or a substituent of a heterocyclic group; R12 is selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -c(0)0R15, -0C(0)R15, _0(CH2)nC(〇)〇Rl5, _ (CH2)nC(〇)〇Rl5, -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 or -S (0)0NRi6Ri7, wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Base, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(〇)〇R15, —〇c(〇)r15, -0(CH2)nC(0)0R15. -(CH2 nC(0)0R15 &gt; -C(0)R15, -NHC(0)R15 &gt; -S(0)PR15, -NR16R17, -〇C(〇)NRl6R17, -C(〇)NR16R17 or -S (0) Substituted by a substituent of 0NR16R17; From a hydrogen atom, a county, a secret group, a heterocyclic group, a silk or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is further selected from one or more selected from the group consisting of _ Substituted with a substituent of a hydroxy group, a cyano group, a nitro group, an alkoxy group or an alkyl group; R16 and R17 are each independently selected from a hydrogen atom, a 素素, an alkyl group, an alkoxy group, a decyl group, a heterocyclic group, and an aromatic group. Or a heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a thiol group, a nitro group and a nitro group. , alkoxy group, alkyl group, ring-based group, heterocyclic group, aryl group, heteroaryl group, -C(〇)〇r15, —〇c(〇)r15, -0(CH2)nC(0)0R15, -(CH2)nC(〇)〇Rl5, _c(〇)Rl5, _NHC(〇)Rl5, -S(0)PR15, -NR18R19, -0C(0)NRlY9, _c(9)nr18r19 or -s(o)onr18r19 Substituted; 95255 62 201242964 or 'R16 and R17 form a heterocyclic group with a nitrogen atom attached thereto, wherein the heterocyclic group contains one or more N, 0 or s(0)P heteroatoms, and The hetero group needs to be further protected by one or more dentates, meridons, and cyano groups. , cleavage group, alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, ~C(〇)OR15, -〇C(〇)Rl5, 〇(CH2)nC(〇) 〇Rl5, _(CH2)nC(〇)〇Rl5, 〜C(〇)Ri5, _NHc(〇)r15, —s(〇)pRl5,—serving i8r19, —〇c(8)nr18r19, C(0)nr18r19 or ~S (〇) Substituted by a substituent of NR18R19; A R18 and R19 are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterofluorenyl group, an aryl group or a heteroaryl group; η is selected from 1 '2 or 3 And Ρ is selected from 0, 1 or 2. A preferred embodiment of the invention is a compound of the formula (ΙΑ) or (ΙΒ) or a pharmaceutically acceptable salt thereof, wherein ^ and ρ are selected from an alkyl group or an aryl group. A preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the carbon atom to which they are attached form a cyclopropyl group. A preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R6 is selected from the group consisting of ruthenium atoms. A preferred embodiment of the invention, a compound of the formula (IA) or (IB), wherein R12 is selected from a nitrogen atom or a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof. Equivalents considered - one of ordinary skill in the art will appreciate that compound (IA) may also exist in the form of tautomers. The tautomeric form of the compound (IA) may include, but is not limited to, the structure represented by the following formula (IB): 63 95255 6 6201242964 N-R6 N- Ύ f^NH J i X!n R2> R 4NR5 r3 RR ί R4 R' (IA) (IB) All such tautomeric forms are included within the scope of the invention and are inherently included in the definition of compound (IA). Typical compounds of the compound of the formula (IA) or (IB) include, but are not limited to: the compound numbering structure named lc, NH 対H 5', 6'-dioxaxyspiro [cyclopropane-1,3'-isoindole Porphyrin]-indole-imine 7d, NH 5',6'-diethoxyspiro[cyclopropane-1,3'-isoindoline]-quinone-imine 9f 2,5-dimethyl- 5_phenyl_6 in ° ratio ρ and [3, 4-Ζ?] π ratio bite-7-imine 24d f nh2 5,6-diethoxy-7-fluoro-3,3_didecyl -isoindole-1-amine 36d •r nh2 5,6-diethoxy_3,3_diethyl gas-iso, alpha-1-amine 41g 5',6'-diethoxy- 7'-Fluoro-spiro[cyclopropane-1,3'-isoindoline]-oxime-imine 58f 1 2-decyloxy-5-mercapto-5-phenyl-6 and -D ratio ρ And [3, 4-/?]° ratio -7-imine 64 95255 201242964 p〇〇〇C^cSh 1-mercapto-1-phenyl-2 and -〇 ratio A and [3,4 -Z?]quinoline-3-imine or a pharmaceutically acceptable salt thereof. The present invention relates to a process for the preparation of a compound of the formula (IA) or (IB), which process comprises:

R3 R4 R (III)

The dithizone solution of the compound of the formula (III) is heated in the presence of cuprous cyanide and cuprous iodide to obtain a compound of the formula (IA) or (IB);

Alternatively, the compound of the formula (IV) is mixed with a format reagent and a titanate under ice bath, and stirred at room temperature to obtain a compound of the formula (IA) or (IB);

(V) Alternatively, a compound of the formula (V) is reacted with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB);

65 95255 201242964 Alternatively, a tetrahydrofuran solution of the compound of the formula (v i) can be stirred in the presence of water and triphenylphosphine at room temperature to give a compound of the formula (IA) or (IB). Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another aspect of the invention relates to the use of a compound of the formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, for the preparation of a calcium ion transport inhibitor. Another aspect of the invention relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a thrombin receptor antagonist, wherein said thrombin receptor antagonizes The agent is a PAR1 receptor antagonist. The present invention relates to the use of a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a platelet aggregation inhibitor. The present invention relates to the use of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for a smooth muscle cell proliferation inhibitor. The present invention relates to the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for treating a thrombin receptor-related disease, wherein the thrombin receptor Related diseases are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, generalized intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, kidney Small ball nephritis, osteoporosis, god 66 95255 201242964 by disease and / or malignancy. The present invention relates to a method of inhibiting calcium ion transport comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The present invention relates to a method for inhibiting a thrombin receptor, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the thrombin The receptor is the PAR1 receptor. # The present invention relates to a method for inhibiting platelet aggregation comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The present invention relates to a method for inhibiting proliferation of smooth muscle cells, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The present invention relates to a method for treating a disease associated with a thrombin receptor, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination containing the same The thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, generalized intravascular coagulation syndrome, hypertension, inflammation Sexual diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological diseases and/or malignant tumors. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting calcium ion transport. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 67 95255 201242964 as a drug for inhibiting a thrombin receptor whose blood enzyme receptor is a PAR1 receptor. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting platelet aggregation. Each of the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting proliferation of smooth muscle cells. The present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is a medicament for treating a thrombin receptor-related disease, wherein the thrombin receptor-related disease is selected from the group consisting of Thrombosis, 'vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, generalized intravascular coagulopathy, hypertension, inflammatory disease, rheumatism, asthma, glomerular inflammation, f quality osteoporosis, neurological diseases and / or malignant tumors. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the terms used in the specification and claims have the following meaning. "Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of up to 20 carbon atoms. Preferred are alkyl groups having from 12 to 12 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, and Pentyl, M_dimethylpropyl, 1,2-dimercaptopropyl, 2,2-dimethylpropyl, 丨_ethylpropyl, 2-methylbutyl, 3-mercaptobutyl Base, n-hexyl, puethyl 2 - decyl propyl, i 12, monodecyl propyl, 1,1-didecyl butyl, 1,2-didecyl butyl, 2, 2-didecyl Butyl, 1,3-dimercaptobutyl, 2-ethylbutyl, 2-mercaptopentyl, 95255 68 201242964 3-methylpentyl, 4-methylpentyl, 2,3-dimethyl Butyl, n-heptyl, 2-decylhexyl, 3-decylhexyl, 4-decylhexyl, 5-decylhexyl, 2,3-dimercaptopentyl, 2,4-didecylpentane Base, 2, 2-dimercaptopentyl, 3, 3-dimercaptopentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-didecylhexyl, 2 , 4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-didecylhexyl, 3,3-dimercaptohexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl , 2-mercapto-3-ethylpentyl, n-decyl, 2-mercapto-2-ethylhexyl, 2-mercapto-3-ethylhexyl, 2,2-diethylpentyl, N-decyl, 3, 3-diethylhexyl, 2,2-diethylhexyl' and its various branched isomers, etc. More preferred are lower alkyl groups containing from 1 to 6 carbon atoms, non-limiting examples including mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec. Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimercaptopropyl, 1-ethylpropyl, 2-mercaptobutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimercaptopropyl, 1,1-didecyldin φ, 1,2- Dimercaptobutyl, 2,2-didecylbutyl, 1,3-dimercaptobutyl, 2-ethylbutyl, 2-mercaptopentyl, 3-mercaptopentyl, 4-anthracene A pentyl group, a 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkene. Alkyl, alkynyl, alkoxy, alkylthio, alkylamino, dentate, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carbonyl, -C(0)0R15, -0C(0)R15, -0(CH2)nC(0)0R15, -(CH2 nC(0)0R15, -C(0)R15, 69 95255 201242964 -NHC(0)R15, -S(0)PR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 or -S (0) 0NR16R17. "Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 Up to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. 7Γ electronic system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkane, depending on the number of common spiro atoms between the ring and the ring. base. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more A double button, but none of the rings have a fully shared 7-inch electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 70 95255 201242964 members. Depending on the number of constituent rings, it may be classified into a bicyclic ring, a tricyclic ring, a tetracyclic ring or a polycyclic ring. The fused % group is preferably a bicyclic ring or a tricyclic ring, more preferably a 5 member/5 member or a 5 member member/6 member bicyclic alkyl group. Non-limiting examples of reticulated groups include

Bridge 裒 基 私 私 5 5 to 20 members, any two rings share two not directly

All-carbon polycyclic groups of attached carbon atoms, these may contain one or more double bonds 'but no-rings have a complete (d) electronic system. It is preferably 6 to 14 members' more preferably 7 to 1 () members. The ring may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring according to the number of constituent rings, preferably a double ring, a triple coat or a fourth percent, more preferably a double loop or a tricyclic ring. A non-limiting example of a bridged alkyl group comprising a ruthenium pair of 4 4 to r can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the bond to the parent, The resulting ring is a cycloalkyl group, and non-limiting examples include indane, tetrahydronaphthyl 'benzo ring bases, and the like. The ring may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a group, a dilute group, an alkynyl group, an alkoxy group, Alkylthio, alkylamino, dentate, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, hetero, WE, heterocyclic 71 95255 201242964 alkoxy, Ring-burning sulfur group, heterocyclic sulfur-burning group, several groups, _C(〇)〇R15, -0C(0)R15, -0(CH2)nC(0)0R15, -(CH2)nC(0)0R15,- C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -〇c(〇)NR16R17, -C(0)NR16R17 or -S(0)0NR16R17. A dilute group refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, a vinyl group, a fluorene-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, and the like. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(0)0R15, -〇C(0)R15, -〇(CH2)nC(0)OR15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -0C(0)NR16R17, -C(0)NR16R17 or -S(〇)〇NR16R17. An alkynyl group refers to an alkyl group as defined above which consists of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, propynyl, 2-propynyl, 1-, 2- or 3-butynyl. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, and a sulfur-burning group. , amphoteric, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio Heterocyclic sulfur group, -C(0)0R15, -〇C(〇)R15, -〇(CH2)nC(0)OR15, -(CH2)nC(0)0R15, -C(〇)R15, -NHC(0)R15, -S(0)PR15, -NR1%", -0C(0)NR16R17, -C(〇)NR16R17 or -S(0)0NR16R17. 72 95255 201242964 Substituting A heterozygous rf Or partially unsaturated monocyclic or polycyclic cyclic hydrocarbons =, =() to (: °Γ" sub-', + one or more ring atoms =: two ring atoms, of which ... == its -.* ^ Chinyl morpholinyl, thiomorpholine

Base ^ Chenzin base. The polycyclic cycloalkyl group includes a heterocyclic group of a spiro ring, a fused ring, and a bridged ring. "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or more ring atoms: from = subtraction (where ρ is an integer) The remaining hetero atom of G to 2) is a slave. Some may have one or more double bonds, but none of them have a completely common π-electron system. Preferably, 6 to 14 members, more preferably 2 7 to 10 members. The spiroalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group, preferably a monospiroalkyl group, depending on the number of common snail atoms between the ring and the ring. Double spiral wire. More preferably 4 members / 4 Μ, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the single screw base. Embodiment includes

A fused heterocyclyl refers to 5 to 20 members, each ring in the system shares a contiguous pair of atomic polycyclic heterocyclic groups with other rings in the system, one or more rings 73 95255 201242964 may contain one or more Double bond, but none of the rings have a fully conjugated 7-inch electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0)p (where P is an integer from 0 to 2) heteroatoms, and the remaining ring atoms For carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member double ring heterogeneous Ring base. Non-limiting examples of fused heterocyclic groups include

"Bridge heterocyclyl" refers to a 5 to 14 member, any two rings sharing two polycyclic heterocyclic groups of atoms that are not directly bonded, these may contain one or more double bonds, but none of the rings are fully conjugated A 7-inch electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0)P (wherein ρ is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or multi-ring bridge ring bases, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. A non-limiting example of a bridged cycloalkyl group comprises: 74 95255 201242964 The heteromonyl ring may be slightly bonded to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group. Non-limiting examples include:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, • hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocyclic thiol, carbonyl, -C(0)0R15, -〇C(〇)R15,-0(CH2)„C(0)0R15, -(CH2)nC(0)〇R15 -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -〇c(0)NR16R17, -c(o)nr16r17 or -s(o)onr16r17. Aryl a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a polycyclic ring of a conjugated π-electron system (ie, a ring with adjacent pairs of carbon atoms) a group, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring is bonded to the parent structure As an aryl ring, non-limiting examples include:

The aryl group may be substituted 13⁄4 unsubstituted, and when # is substituted, the substituent is preferably one or more of the following groups than 95255 75 201242964, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane. Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, -C(0)OR15, -〇C(0)R15, -0(CH2)nC(0)0R15, -(CH2)nC(0)0R15, -C(0) R15, -NHC(0)R15, -S(0)pR15, -NR16R17, -〇C(0)NR16R17, -c(o)nr16r17 or -s(o)onr16r17. "Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably 6 to 1 member. It is preferably 5 or 6 members such as fluorenyl, stilbene, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group The ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group may be optionally substituted or unsubstituted, and when # is substituted, the substituent is preferably one or more of the following groups H selected from the group consisting of a group, an alkynyl group, an alkoxy group, a sulfur-burning group, Amine, halogen, thiol, thiol, sulfhydryl, cyano, hetero, heterocycloalkyl, aryl, heteroaryl alkoxy, heteroweixy, thiol, thiol, (10)(10)/, -0C(0)R^-0(CH〇nC(0)0R^^(CH〇nC^ 95255 76 201242964 -NHC(0)R15 &gt; pi5 _\Tpl6nl7 )pR _NR R '-0C( 0) NR16R17&gt;-C(0)NR16R1 or -S(0)0NR16r17. Let xbPI oxy group #-Q_(filament) and _Q~(unsubstituted cycloalkyl group), n ^ ΐ meaning as described above. Limiting the _ contains methoxy, its oxy, butoxy, S propoxy, cyclobutoxy, cyclopentyloxy dihydrazide, -yl, etc. The alkoxy group may be substituted or unsubstituted as needed When the field is substituted, the substituent is preferably one or more of the following groups,

Also k is a decyl group, an alkenyl group, an alkynyl group, an alkoxy group, a thiol group, an alkylamino group, an i group, a thiol group, a thiol group, a thio group, a cyano group, a cycloalkyl group, a heterocyclic fluorenyl group, Aryl, heteroaryl, valoxy, heteroweiloxy, cyclomethanyl, heterocycloalkylthio, -C(0)0R15, _0C(0)R15, _〇(CH〇nC(〇)〇Rl5 , -(CH2)„C(0)0R15. -c(〇)R^. _NHC(〇)r«5&gt; _s(〇)pR,5_nr16r17 -0C(8)NR R17,~c(0)NR16R17 or -s(0 0NR16R17. "Mercaptoalkyl" means that the hydrogen in decane (SiH4) is replaced by one or more alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, cycloalkyl or heterocyclic groups. An organic alkyl group in which an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkoxy group, a cycloalkyl group, a heterocyclic group may be optionally substituted or unsubstituted, when substituted, The substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkoxy, _, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, Carbonyl group, -C(0)0R15, -0C(0)R15, -0(CH2)nC(0)0R15, -(CH2)„C(0)0R15, -C(〇)Ri5, -NHC(0) R15' -S(0)pR15' - NR16R,7'-0C(0)NR16R17'-C(〇)Nri6Riv or -S(0)0NR16R17. Non-limiting examples include trimethyl sulfhydryl, dimethylethyl sulphate, tri-tert-butyl stellite "Hydroxy", such as fluoro, chloro, bromo or moth. "Amine", "hydroxy" refers to the group -OH. Refers to -nh2. "Cyano" refers to -CN. Shishaji refers to -N〇2. "Urotropine" refers to hexamethylenetetramine. The alkyl group is substituted by a radical.

"Lawson's reagent" means - 〇 〇 -.

"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. . "Pharmaceutical composition" means a mixture comprising one or more compounds herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity. m, η, p and R15 to R17 are as defined in the compound of the formula (I). Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention employs the following technical solution: 78 95255 201242964 A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the present invention comprises the following steps:

(IA) (IB) (1C) (I) A solution of a compound of the formula (IA) or a compound of the formula (IB) in tetrahydrofuran is reacted with a compound of the formula (1C) at room temperature to give a formula under triethylamine conditions. _ (I) a compound; a process for the preparation of a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, comprising the steps of:

N,

The dimethyl sulfoxide solution of the compound of the formula (II) is heated in the presence of cuprous cyanide and cuprous iodide to obtain a compound of the formula (IA) or (IB);

Alternatively, the compound of the formula (III) is mixed with a format reagent and titanate under ice bath, and stirred at room temperature to obtain a compound of the formula (IA) or (IB); 79 95255 201242964

Or 'reacting a compound of the formula (ιν) with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB);

(V) ('A) (IB) or a solution of the compound of the formula (V) in tetrahydrofuran in the presence of water and triphenylphosphine at room temperature to obtain a compound of the formula (IA) or (IB). Wherein X is selected from the group consisting of halogen' is preferably a gas atom or a bromine atom; and L, γ and R to R are as defined in the formula (I). The following examples are provided to further describe the present invention, but these examples are not intended to limit the scope of the invention. EXAMPLES The structure of the compound was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is presented in units of parts per million (卯m). The nmr was measured by Bruker AVANCE-400 nuclear magnetic instrument. The solvent was deuterated dimethyl sulfoxide (DMSO-i/6), deuterated gas (CDCh), deuterated sterol (CHsOD), internal standard was four. Methyl decane (TMS), chemical shifts are presented in units of 1 〇, 卯.... 95255 80 201242964 MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX). The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4. 6 mm color column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 parent 4.6111111 chromatography column). 1C5. The value was determined using a NovoStar plate reader (BMG, Germany). The TLC plate is made of Yantai Yellow Sea HSGF254 or Qingdao GF254 Silicone Sheet. The specifications of the silica gel plate used for thin layer chromatography (TLC) are # 0. 15 mm to 0.2 mm, and the specifications for the separation and purification of thin layer chromatography are used. It is 0. 4 mm to 0. 5 mm. Column chromatography is generally carried out using Yantai Huanghai Shixijiao 200~300 mesh Shiqi gum as carrier. The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH &amp; Co. KG, Aei*as Organics 'Aldrich Chemical Company, 韶远化学科技 φ (Accela ChemBio Inc., Dari Chemicals and other companies. Unless otherwise specified in the examples, they were all carried out under a nitrogen atmosphere or an argon atmosphere. Rat air or gas is the reaction bottle connection. A nitrogen or nitrogen balloon of about 1L volume. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus. The deuteration reaction is usually evacuated and charged with hydrogen' repeated three times. The microwave reaction used a CEM Discover-S Model 908860 microwave reactor. 95255 201242964 There is no special description in the examples, and the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. The optimum reaction temperature at room temperature is 2 (TC to 30 ° C. The progress of the reaction in the examples is monitored by thin layer chromatography (TLC), and the system of the developing solvent used for the reaction is: dioxane and The sterol system, n-hexane and ethyl acetate system 'petroleum ether and ethyl acetate system, propylene carbonate, the volume ratio of the solvent is adjusted according to the polarity of the compound. The purified compound is used in the column chromatography eluent system and thin The system of the layer-developing solvent includes: A: a two-gas methane and methanol system, b: a n-hexane and ethyl acetate system, C: an ethyl acetate and a decyl alcohol system, and d: a normal hexane 'E: ethyl acetate, The volume ratio of the solvent is adjusted depending on the polarity of the compound. It may also be adjusted by adding a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid. Example 1 1-(3, 5-tert-butyl-4- Phenyl)-2-(3'-imino-5' 6, _-decyloxy-spiro[cyclopropane-1,1'-isoindoline]-2,-yl)ethanone hydrogen Acid star

82 95255 201242964 First step 4, 5-Dimethoxy phthalonitrile Dissolve 1,2-dibromo-4,5-dimethoxy phenylbenzene (20.01 g, 68 mmol) in 100 mL of N,N-dioxin To the carbamide, copper cyanide (24. 00 g, 272 mmol) was added, and the reaction was stirred at 150 ° C for 1 hour, and the reaction was further stirred at 170 ° C for 5 hours. The reaction solution was poured into 100 mL of aqueous ammonia, 400 mL of ethyl acetate was added, filtered, and the filter cake was washed with ethyl acetate (100 mL×6). The filtrate was extracted with ethyl acetate (200 mL×2), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5-Dimethoxy phthalic acid lb (4.50 g, white solid), yield: 35.0%. Brilliant R (400 MHz, CDC13, ppm): δ 7.20 (s, 2H), 4. 01 (s, 6H) Second step 5',6'-dioxaxyspiro[cyclopropane-1,3 '-Isoporphyrin]-oxime-imine oxime bromide, 4,5-didecyloxyphthalonitrile 11) (0.94 d, 5 〇1) was dissolved in 50 mL of diethyl ether. 5小时。 Adding tetrahydrogen vinegar tetraacetate (1. 65mL, 5.58mmol) and ethyl bromide (3. 70mL, 11. lOmmol), the reaction was stirred for 2.5 hours. To the reaction mixture was added 55 mL of decyl alcohol, and the residue obtained was purified by eluent column chromatography using eluent system A to give the title product 5',6'-dimethoxyspiro[cyclopropane-1,3'- Porphyrin]-indole-imine hydrobromide lc (407 mg, brown solid), yield: 37.3%. MS m/z (ESI): 219 [M+l] R R (400 MHz, DMSO-A, ppm): δ 10.37 (Z?r. s,1H), 83 95255 201242964 9. 39(Z?r s, 1H), 9. 15 (Z?r. s, 1H), 7. 88 (s, 1H), 7.06 (s, 1H), 4. 96(m, 3H), 3. 83 (s, 3H), 1.78(m, 2H), 1.64 (m, 2H) Step 3 2-Bromo-l-(3' 5-di-tert-butyl-4-hydroxyphenyl)ethanone dry ice-acetone bath, Gasified aluminum (16 〇〇g, 〇.12m〇1) was dissolved in 150 mL of chlorodecane, followed by the addition of bromoethene gas (1 〇, 0.12 mol) and 70 mL of 2'6-di-tert-butyl A solution of phenol ld (24 5 〇g, 0.12 mol) in dichloromethane was stirred for 1 hour. 300 mL of ice water was added to the reaction solution, and the aqueous phase was washed with methylene chloride (10), and the organic phases were combined and washed successively with saturated sodium hydrogen carbonate solution (2〇〇raLx3) and saturated sodium chloride solution (200 inLx3) Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure, and purifying the obtained residue by eluent column chromatography with eluent column chromatography to give the title product 2-bromo-1-(3,5-di-tert-butyl- 0%。 4-hydroxyphenyl) ethyl ketone lf (28 g, yellow solid), yield: 72.0%. MS m/z (ESI): 326 [Ml] Η NMR (400 MHz, CDCla, ppm): δ 7. 89 (s, 2H), 5 84 (br s, 1H), 4.40 (s, 2H), 1.48 (s, 18H) The fourth step 1-(3,5-di-tert-butyl-4-phenylphenyl)-2-(3'-imino]5,6, _dimethoxy- Spirulina [cyclopropanone-1, Γ-isoindole]-2'-yl) ethyl ketone hydrogen oxalate salt 5',6'-dimethoxy snail [cyclopropane-1,3'-iso π The noise-inducing imine nitrogen sulphate lc (223ing, 1 · 02ππηο1) is dissolved in four gas cough, adding 2-di-1-(3, 5-di-tert-butyl-4-ylphenyl) Acetyl 95 95 84 201242964 (398 mg, 1.22 mmol) and triethylamine (0.15 mL, 1.08 mmol) were stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (5 mL×2), water (3 mL×2) and ethyl acetate (0. 5mL×2) and dried in vacuo to give the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl) )-2-(3'-imino-5,6,1-dimethoxy-spiro[cyclopropane-1,1 '-isoindoline]-2 '-yl)ethanone hydrogen oxalate 1 (138 mg, yellow solid), 29.1%. MS m/z (ESI): 465 [M+l] 'H NMR (400 MHz, DMSO-i/e, ppm): 6 9.64 s ijj) _ 9. 08 {br. s, 1H), 7. 86 (Z?r. s, 1H), 7. 85 (s, 1H) 7 82 (s, 2H), 7.02 (s, 1H), 5.17 (s, 2H), 3.92 (s, 3H), 3. 83 (s, 3H), 1.66 (m, 4H), 1.44 (s, 18H) Example 2 1-(3-tert-butyl-4-decyloxy-5-morpholinylphenyl)-2-(3, _imino-5,6-dimethoxy-spiro[cyclopropanone- 1,1'-iso. π 朵朵琳]_2'_yl) ethyl ketone hydrobromide

95255 85 201242964 First step 1-(3-tert-butyl-4-hydroxyphenyl)ethanone dry ice-acetone bath, dissolving aluminum oxide (71() g, 0 53m〇1) in 250mL-chloroform During the calcination, 2-tert-butyl-benzene (81.6 mL, 0.53 mol) was added, and the mixture was stirred for 2 hr, and then acetonitrile 2b (37. 9 mL, 0.53 mol) was added dropwise, and the reaction was further stirred for 1 hour. To the reaction mixture was added EtOAc (3 mL). 30/〇. MS m/z (ESI): 191 [Ml] Step 2 1-(3-tert-butyl-4-hydroxy-5-iodo-phenyl)ethanone 1-(3-tert-butyl-4-hydroxyl Phenyl)ethanone 2C (16.2 g, 84. 3imo1) was dissolved in 200 inL, and N-molydimidine diamine (20. 9 g, 92.8 mmol) was added, and the reaction was stirred for 4 hours. The organic layer was combined with ethyl acetate (50 mL×3). The filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting from EtOAc EtOAc EtOAc EtOAc EtOAc g,Yellow solid), Yield: 60. 0%. MS m/z (ESI): 317 [Ml] &lt;RTI ID=0.0&gt;&gt;&gt; {br. s, 1H), 2. 55 (s, 3H), 1.48 (s, 9H) 95255 86 201242964 Step 3 1 (3-tert-Butyl-5-iodo-4-methoxyphenyl) I-(3-tert-butyl-4-hydroxy-5-iodo-phenyl)ethanone 2d (16.1 g, 5 lmmol) was dissolved in 200 mL of acetone at 25 ° C, and potassium carbonate was added (21 14 g, 153 mmol) and iodonane (18 g, i27 mmol) were stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc (EtOAc (EtOAc) 14. g, 14. g, light yellow oil), yield: 84.5%. Lu H NMR (400 MHz, CDCh, ppm): δ 8.25 (d, / = 2. 0 Hz, 1H), 7. 94 (d, / = 2. 0 Hz, 1H), 3. 93 (s, 3H ), 2. 54 (s, 3H), 1.39 (s, 9H) Step 4 1-tert-Butyl-5-(1,1-dimethoxyethyl)-3-iodo-2-indoleoxy Benzene 1-(3-tert-butyl-5-iodo-4-oxophenyl)ethanone 2e (2.6 g, 7.83 mmol) and tridecyl orthoformate (2. 49 g, 23.5 mol) Dissolved in 2. 6 mL of methanol, D(+)-l〇-camphoric acid (9 lmg, 〇. 39 mmol) was added, and the reaction was stirred for 12 hours. 217 mg of carbonic acid was added to the reaction solution, and the mixture was mixed with 0.5 mL of 1 mL of water and 1 mL of hexane. The aqueous phase was extracted with hexane (20 mL×3). The combined organic phase was washed with saturated sodium carbonate solution (10 mL×3). Drying with anhydrous sodium sulfate 'filtered, and the filtrate was concentrated under reduced pressure to give the title product 1-t-butyl-5-(1,1-dimethoxyethyl)_3-moth-2-nonyloxybenzene 2f (2) 3克。 Light yellow oil), yield: 79.3%. ΐ PiMR (400 MHz, CDCh, ρρπι): δ 7.82 (d, / = 2.0 Hz 1H), 7.41 (d, /= 2.0 Hz, 1H), 3.89 (s, 3H), 3. 18 (s, 87 95255 201242964 6H), 1.51 (s, 3H), 1.40 (s, 9H) Step 5 4-[3-tert-Butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene ]]-morpholine 1-tert-butyl-5-(1,1-dimethoxyethyl)-3-iodo-2-methoxybenzene 2f (3.3 g, 8.73 mmol) and 2 -Dicyclohexylphosphino-2'-(N,N-diamino)-biphenyl (172 mg, 0.44 mmol) was dissolved in 33 mL of toluene, palladium on carbon (330 mg, 10%), tert-butanol Sodium (i.68 g, 17.46 mmol) and morpholine (1.52 g, 17.46 mmol) were stirred at 60 ° C for 3 hours. 100 mL of water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (5 mL mL), and the organic phase was combined, washed with saturated sodium sulfate solution (2 〇mL×2), dried over anhydrous sodium sulfate and filtered. The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) 0%。 The morpholine 2g (1.5 g, brown oil), yield: 51.0%. MS m/z (ESI): 338 [M+l] Step 6 2-bromo-1-(3-tert-butyl-4-decyloxy-5-morpholinylphenyl)ethanone 4-[3 -tert-butyl-5-(1,1-dimethoxyethyl)_2-methoxyphenyl]-mole 2g (1.5 g, 4.45 mmol) dissolved in i8 mL of acetic acid, added tribromide Pyridine rust salt (1.57 g, 4.90 mmol), and the reaction was stirred for 2 hours. To the reaction mixture, 30 mL of water was added, and the aqueous layer was extracted with ethyl acetate (2 mL mL), and the organic phase was combined, washed with saturated sodium sulfate solution (1 mL mL), dried over anhydrous sodium sulfate The residue obtained was purified by column chromatography on eluent column chromatography to afford the title product: 2-bromo-br. (3-tert-butyl 8S 95255 201242964 -4- methoxy-5-morpholinyl phenyl) ethyl ketone 2h (930mg, pale yellow solid), yield: 54.6 ° / 〇. MS m/z (ESI): 370 [M+l]^ NMR (400 MHz, CDCh, ppm): 5 7.70 (d, / = 2. 0 Hz, 1H), 7.52 (d, /= 2.0 Hz, 1H ), 4.41 (s, 2H), 4. 〇l(s, 3H), 3.90 (m, 4H), 3.09 (m, 4H), 1.40 (s, 9H) Step 7 1-(3-tert-butyl -4-decyloxy-5-morpholinylphenyl)-2-(3'-iminoamino-5-5,6'-dimethoxy-spiro[cyclopropane-1,1'-isoindole Phenyl]-2'-yl)ethanone hydrobromide salt 5',6'-dimethoxyspiro[cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide lc (229 mg, 1.05 mmol) was dissolved in 4 mL of tetrahydrofuran, and 2-bromo-1-(3-tert-butyl-4-decyloxy-5-morpholinylphenyl)ethanone was added for 2 h (440 mg, 1.19). Methyl) and triethylamine (0.2 inL, 1.44 mmol) were stirred for 12 hours. Filtration, the filter cake was washed with hexane (5 mL), EtOAc (EtOAc (EtOAc) -Mallinylphenyl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl) Ketone hydrobromide 2 (168 g, light yellow powder), Yield: 31.5% MS m/z (ESI): 508 [M+l] R (400 MHz, DMSO-i/e, ppm): δ 9.71 (Z?/·. s, 1H), 9. 13(Z?r. s, 1H), 7. 91 (s, 1H), 7.62 (d, /= 1.6 Hz, 1H), 7.55 (d, /= 1.6 Hz, 1H), 7.08 (s, 1H), 5.34 (s, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.91 (s, 3H), 3.88 89 95255 201242964 (m, 4H), 3.03 (m, 4H), 1.66 (m, 4H), 1.39 (s, 9H) Example 3 l-(3-tert-butyl-4-methoxyphenyl)-2-(3, one Imino-5',6,-dimethoxy-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide

The first step of 1-(3-tert-butyl-4-methoxyphenyl)ethanone is 1-(3-tert-butyl-4-hydroxyphenyl)ethanone 2c (6.3 g, 32. 8 mmol Dissolved in 50 mL of acetone, potassium carbonate (13.6 g, 98.4 mmol) and methyl iodide (11.65 g, 82 mmol), 5 (TC stirring reaction for 2 hours. Filtration, filtrate concentrated under reduced pressure, 50 mL water and 50 mL Dihydromethane, liquid separation, organic phase washed with saturated sodium carbonate solution (2 〇mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1_(3_tert-butyl-4- oxyloxy Ethyl ketone 3a (6.0 g, white solid), yield: 88.6%.] NMR (400 MHz, CDCh, ppm): δ 7.99 (d, / = 2. 〇Hz 1H), 7.87 (dd, //= 8. 4 Hz, Λ = 2. 0 Hz, 1H), 6.94 (d /= 8.4 Hz, 1H), 3.97 (s, 3H), 2.60 (s, 3H), 1.46 ( s 9H) Second step 90 95255 201242964 2-Bromo-i-(3-tert-butyl-4-methylmethoxyphenyl)ethanone 1 (3~-tert-butyl-4-methoxyphenyl) Ethyl ketone 3a (1 Og 4.8 〇 〇 1) was dissolved in 8 mL of acetic acid, added to the three desert _ (1'6 g 5 · 04_ 〇 1), the secret reaction 3.5 hours. Concentrated under reduced pressure, add - into Apply 1 water and ancestor ethyl acetate, The liquid 'aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phase was combined, washed with saturated sodium carbonate solution (2 〇mU3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the titled product: EtOAc (EtOAc: EtOAc) R (400 MHz, CDCla, ppm): δ 8.02 (d, / = 2 0 Hz 1H), 7.91 (dd, Ji - 8.8 Hz, J2 = 2.0 Hz, ih), 6.97 (d, /= 8.8 Hz, 1H), 4.44 (s, 2H), 3.97 (s, 3H), 1.44 (s, 9H) The third step of the spring 1-(3-tert-butyl-4-methoxyphenyl)-2-(3' -Imino-5,6,2-dimethoxy-spiro[cyclopropane-1, fluorene-isoindolyl]-2'-yl)ethanone hydrobromide 5',6'-di Methoxyspiro[cyclopropane-1,3'-isoindolyl]-oxime-imine hydrobromide lc (240 mg, 1.1 mmol) was dissolved in 3 mL of tetrahydrofuran and 2-bromo-1-( 3-tert-Butyl-4-decyloxyphenyl)ethanone 3b (360 mg, 1.26 mmol) and triethylamine (3 mL, 2.16 mmol). Filtration, the filter cake was washed with hexane (5 mL EtOAc) (EtOAc) -2-(3'-imino-5',6' _二曱91 95255 201242964 oxy-spiro[cyclopropan-i,r-iso ahlin]_2,-yl) acetamidine 3 (287 mg, pale yellow powder), Yield: 61.7% MS m/z (ESI): 423 [M+l] NMR (400 MHz, DMSO-form, ppm): s 9 68 (Knowledge &amp; ih) 9.14 (br. s, 1H), 8.00 (dd, /, = 8. 8 Hz, J2 = /. 6 ^ 1H), 7. 88 (s, 1H), 7.86 (d, / = l· 6 Hz ,1H), 7. 21 (d / = 8. 8 Hz, 1H), 7. 08 (s, 1H), 5. 18 (s, 2H), 3 92 (s' 3H), 3.91 (s, 3H ), 3.87 (s, 3H), 1.73 (m, 4H), 1 39 (s, 9H) Example 4 (3-bromo-5-tert-butyl-4-hydroxyphenyl)-2-(3' -imino-5, ketohydrobromide 曱oxyspiro[cyclopropane-1,1'-isoindoline]_2,_yl)

The first step 1-(3-di-5-tert-butyl-4~hydroxyphenyl)-ethanone 1-(3-tert-butyl-4-hydroxyphenyl)acetamidine with 2c (6 3 g 32.8 mmol Dissolved in 50 mL of acetonitrile and N,N-dimethylacetamide (V/v 10:1) mixed solvent 'Addition of N-bromosuccinimide (1〇2 57匪〇1), stir the reaction 0.5 hours. Concentration under reduced pressure, the residue obtained was purified by eluent </RTI> </RTI> <RTIgt; 4% (12. ig, white solid), Yield: 85.8%. MS m/z (ESI): 269 [Ml] NMR (400 MHz, CDCI3, ppm): § 8 〇3 (Mountain/= 2.0 Hz, 1H), 7.92 (d, /= 2.0 Hz, 1H), 6. 33 s, 1H), 2.58 (s, 3H), 1.46 (s, 9H) Step 2

2-bromo-1-(3-bromo-5-tert-butyl-4-butylphenyl)ethanone 1-(3-bromo-5-tert-butyl-4-hydroxyphenyl)ethanone 4a ( 5·0 g, 18. 4 mmol) was dissolved in 50 mL of acetic acid, and a tris-pyridinium salt (6·2 g, 19. 4 liters of ol) was added, and the reaction was stirred for 12 hours. The mixture was cooled under reduced pressure, and then 100 mL of water and ethyl acetate (100 mL) was added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×3), and the organic phase was washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was decompressed and reduced, and the residue obtained by purifying the column system chromatography with eluent system B, &amp; product 2-di-1 - (3-di-5-tert-butyl-4-ylphenyl) Gray oil), yield: 99.2%. MS m/z (ESI): 349 [Ml] g, 'Get the title 鲫4b (6 !H NMR (400 MHz, CDCh, ppm): δ 8.07 (dy 1H), 7.57 (d, /= 2.0 Hz, 1H ), 6.41 (br ~~ 2' ° Hz&gt;

s, ^H) A (s, 2H), 1.48 (s, 9H) Λ 4〇 third step 93 9S255 201242964 1-(3-Bromo-tert-butyl-4-hydroxyphenyl)-2-(3,- Imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoporphyrin]-2,-yl)ethanone hydrobromide 5',6,-di曱oxyspiro[cyclopropane-1,3,-isoporphyrin]-oxime-imine hydrobromide lc (228 mg, 1. 05 mmol) was dissolved in 4 mL of tetrahydrofuran. 1-(3-Bromo-5-tert-butyl-4-hydroxyphenyl)ethanone 4b (540 mg, 1.54 mmol) and triethylamine (3 mL, 2.16 mmol). Filtration of the 'filter cake' with n-hexane (i.sub.2 mL), water (5 mL.sup.4) and ethyl acetate (2.times.sup.2), and dried in vacuo to give the title product i-(3-bromo-5-tert-butyl-4-yl) Phenyl)-2-(3,-imino-5',6,-dimethoxy-spiro[cyclopropane-1, oxime-isoindoline]-2'-yl)ethanone hydrobromide Salt 4 (166 mg, pale yellow powder), Yield: 32. 6% MS m/z (ESI): 487 [M+l].H NMR (400 MHz, DMSO-cfe, ppm): δ 9.63 (br. s, 1H), 9. 12 (/? factory s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.05 (s, 1H), 4.95 (s, 2H) ), 3.90 (s, 3H), 3.84 (s, 3H), 1.65 (m, 4H), 1.33 (s, 9H) Example 5 2-[8-tert-butyl-6-[2-(3' - Imino-5',6'-dimethoxy-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethenyl]-2,3-dihydro-1,4 -benzo-oxazin-4-yl]ethyl acetate hydrobromide

94 95255 201242964

First Step ® 1~(3-tert-Butyl-4-yl-5-nitro-phenyl)-ethanone

Dissolve 68% concentrated nitric acid (105 mL, 1.6 mol) in a mixed solvent of 60 mL of dichloromethane and water (V/V = 2:1) at l ° ° C, and add 1-(3-tert-butyl- 5小时。 The reaction was stirred for 1.5 hours. The reaction was stirred for 1.5 hours. After the reaction was stirred for 1.5 hours, 6 mM of ethyl ether, hydrazine, 6 mL of acetic anhydride and 105 mL of concentrated hydrochloric acid were added. Add 200 mL of ice water to the reaction solution, extract with ethyl acetate (15 〇mLx3) and combine the organic phase with saturated sodium bicarbonate to adjust the pH to 5 to 6, and wash with saturated sodium chloride solution (5 〇mLx3) Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure, and purifying the residue obtained by eluent column chromatography to give the title product (3-tert-butyl-4-ylidene-5-decyl) -Phenyl)acetamidine 5a (6·27 g, yellow solid), yield: 39.6%. MS m/z (ESI): 236 [Ml] 4 NMR (10) MHz, DMSO 乂 δ u 4 〇 &&amp; 1H), 8.45 (d, / = 2. 0 Hz, in), 8 〇 8 (Mountain J = 2 〇Hz,1H), 2.59 (s,3H),1.42 (s,9h) 95 95255 201242964 Step 2 1 -[4-(2-Molyoxy)-3-tert-butyl-5-nitro -Phenyl]ethyl@isolated 1-(3-tert-butyl-4-transyl-5-decyl-phenyl)ethanone 5a (6.26 g, 26.4 mmol) in 80 mL of N,N- Adding carbon to dimethyl decylamine

Potassium acid (18.25 g, 132 mmol) and 1,2-dibromoethane (24.8 g, 132 mmol) were stirred at 100 ° C for 10 hours. Concentrate under reduced pressure, add 2 mL of water, extract with ethyl acetate (200 mL×3), and the organic phase is combined, washed with saturated sodium carbonate solution (100 mL×3), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product [4-(2-bromoethoxy)-3-tert-butyl-5-nitro-phenyl]ethanone 5b ( 5.74 g, yellow oil), yield: 48.6%. 4 NMR (400 MHz, DMSO-form, ppm): δ 8. 32 (d, /= 2.0 Hz, 1H), 8. 11 (d, / = 2. 0 Hz, 1H), 4. 25 (in, 2H), 3. 82 (m, 2H), 2.62 (s, 3H), 1.44 (s, 9H) The third step 1 - (8-tert-butyl-3, 4-dihydro Hi, 4-benzo-) Ethyl ketone ketone ketone l-[4-(2- ethoxyethoxy)-3-tert-butyl-5-de-p-yl]ethanone 5b (3. 65 g, 10.6 mmol) The mixture was charged with /carbon (〇5 g, 10%) in 35 mL of toluene, and the reaction was stirred for 40 hours. 30 mL of ethyl acetate was added to the reaction mixture, the mixture was filtered, and the filtrate was evaporated to dryness. Dihydro-2 and -1,4-bromo and chemo-6-yl)ethanone 5c (40 mg, yellow solid), yield: 14.8%. MS m/z (ESI): 234 [M+l] 96 95255 201242964 Fourth Step 2-(6-Ethyl-8-tert-butyl-2,3~dihydro_14_benzoxanthene_4 Ethyl acetate ethyl 1-(8-tert-butyl-3, 4-dialdehyde, 4-benzoxazine-6-yl)ethanone 5c (4.8 g, 20.5 mmol) was dissolved in 8 mL &amp; N-dimethylformamide, potassium carbonate (8.5 g, 61.7 mrool) and ethyl bromoacetate (1) 5 咏 102 mmol) were added to carry out a reaction at 100 ° C for 3 hours. Concentrate under reduced pressure, add 2 〇〇 ' ' water, extract with ethyl acetate (l 〇〇 mL x 3), combine the organic phase, wash with saturated gasification / sodium solution (50 mL x 3), dry over anhydrous sodium sulfate, filtered, filtrate pressure Concentration, the residue obtained was purified by eluent column chromatography eluting with eluent to afford the title product 2-(6-ethylhydrazinyl-tert-butyl-2,3-dihydro-l-benzoxazine-4 -Base) Acetate 5d (4·7 g, yellow solid), Yield: 71.5%. MS m/z (ESI): 320 [M+l].H NMR (400 MHz, DMSO-c/e, ppm). δ 7, n / = 2 0 Hz • 1H), 7. 09 (d, / =2.0Hz, 1H), 5 94 (々rs,1H),4 19 (m,2H),3.32 (m,2H),2.44 (s,3H),1·33 (s,9H) Step 5 -[6-(2-Molybdenum)-8-tert-butyl~2,3_dihydro-indole, 4-benzoxazin-4-yl]ethylidene ethyl ester 2-(6-B Ethyl acetate of 8-8 (t. To the acetic acid, dibromopyridinium salt (8. 18 g, 25.6 mmol) was added, and the reaction was stirred for 5 hours. The organic layer was combined with ethyl acetate (100 mL×3), and the organic phase was combined, washed with saturated chlorinated steel solution (50 mL×3), dried over anhydrous sodium sulfate. The transition, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product 2-[6-(2- oxalyl)-8-tert-butyl-2,3 ~ Dihydro-1,4-benzo- oxomethyl-4-yl]ethyl acetate 5e (3.3 g, brown-black solid), yield: 39.0%. MS m/z (ESI): 400 [M+l] NMR (400 MHz, CDCh, ppm): δ 7.42 (d, / = 2.0 Hz 1H), 7. 13 (d, / = 2.0 Hz, 1H), 4.43 (s, 2H), 4.36 (m&gt; 2H), 4.21 (m, 2H), 4.10 (s, 2H), 3.58 (in, 2H), I.42 (s, 9H), 1.35 (m, 3H) Step 6 2-[8-tert-Butyl-6-[2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane-1,1'-isoporphyrin) ]-2'-yl)ethinyl]-2,3-dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 5',6'-dimethoxy Spirulina [cyclopropane-1,3,-isoindoline]-1,-imine hydrogen&gt; odor acid lc (241 mg, 1. llmmol) was dissolved in 4 mL of tetrahydrofuran, and 2-[6 was added. -(2-Bromoethenyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxazin-4-yl]acetate 5e (708 mg, 1.77 mmol) and triethylamine (0.4 mL, 2.88 mmol), and the reaction was stirred for 12 hours. Filtration, the filter cake was sequentially washed with hexane (10 mL×2), water (5 mL×3) and ethyl acetate (1 mL×2) and dried under vacuum to give the title product 2_[;8-tert-butyl_6_[2_(3,-imine) Base _5,6-monodecyloxy-spiro[cyclopropan-1,1'-iso η 引 u朵淋]-2'-yl)ethinyl]-2,3-dihydro-1,4 - benzoxazin-4-yl]ethyl acetate hydrobromide 98 95255 201242964 5 (142 mg, white powder), yield: 23.9%. MS m/z (ESI): 536 [M+l] 4 NMR (400 MHz, DMSO - also ppm): δ 9 7 〇 (eg s, 1H), 9. 18 (br. s, 1H), 7. 93 (s, 1H), 7. (s? 1H)&gt; 7 n (Sj 1H), 7.08 (s, 1H), 5.14 (s, 2H), 4 32 (tj / = 4. 4 Hz, 2H) , 4. 00 (s, 2H), 4. 14 (q, / = 7. 2 Hz, 2H), 3. 92 (s, 3H), 3.90 (s, 3H), 3. 51 (t, /= 4. 4 Hz, 2H), 1.63 (m, 4H), 1.39 (s, 9H), 1.22 (t, / - γ &lt; 2 Hz, 3H) • Example 6 1-(8-tert-butyl-4- Ethyl-2,3-dihydro~i,4_benzoxazine_6-yl)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropane γ _ 异吲哚啦]-2 base) ethyl ketone hydrochloride

The first step is 1~(8-tert-butyl-4-ethyl_2,3-dihydro-1,4-benzo[0--6-yl)ethanone 1-(8-tert-butyl) 3, 4-dihydro H1,4-1,4-benzo[beta]oxo-6-yl) Ethylene I 5c (1.5 g, 6.4 mmol) is dissolved in 20 mL of hydrazine, hydrazine-didecyl decylamine. Add potassium carbonate (2.66 g, 19.3 mmol) and moth Ethylene (2.6 mL,

32. lmmol), 8 (TC stirred for 12 hours. Concentrate under reduced pressure, add 100 mL of 99 95255 201242964 water, extract with ethyl acetate (l〇〇mLx3) 'The organic phase is combined and washed with saturated sodium chloride solution (50mLx3) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure <yield of the residue obtained from eluent system B with hydrazine column chromatography to give the title product 1-(8-tert-butyl-4-ethyl-2, 3 - dihydro-1,4-benzo-oxazin-6-yl)ethanone 6a (1.0 g, yellow solid), yield: 59. 5% ° MS m/z (ESI): 262 [M+l ] Η 丽 (400 MHz, CDC13, ppm): δ 7.35 (d, /= 2·〇Hz, 1H), 7.29 (d, /= 2.0 Hz, 1H), 4.33 (t, / = 4.4 Hz, 2H), 3.45 (q, /= 6.6 Hz, 2H), 3.40 (t, / = 4.4 Hz, 2H), 2.58 (s, 3H), 1.42 (s, 9H), 1.22 (t, / = 6. 6 Hz, 3H) Step 2 2-Bromo-1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzox-6-yl) Ethyl ketone 1- (8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzo-11 oxo-yl)ethanone 6a (1.0 g, 3.8 mmol) was dissolved in i8 mL of acetic acid and tribromide was added. Pyridine rust salt (1. 28 g, 4. Ommol), 1 〇〇 it disturbed the reaction for 1 hour 0 decompression Concentrated, added 100 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL &lt; 3 &lt; 3) &lt;3 &lt;3&gt;&lt;3&gt;&lt;3&gt;&lt;3&gt; The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product 2-di-b-(8-tert-butyl-4-ethyl-2,3-dihydro-^-benzopyr Pyrazin-6-yl)ethanone 6b (194 mg, yellow solid), yield: 29 2%. MS m/z (ESI): 340 [M+l] 95255 100 201242964 ^ NMR (400 MHz, DMSO-, Ppm): δ 7. 38 (d, /= 2.0 Hz, 1H), 7.30 (d, /= 2.0 Hz, 1H), 4.45 (s, 2H), 4.35 (t, /= 4.4 Hz, 2H), 3.45 (m, 2H), 3.41 (t, / = 4.4 Hz, 2H), 1.42 (s, 9H), 1.22 (in, 3H) Step 3 1-(8-tert-butyl-4-ethyl-2, 3-Dihydro-1,4-benzo.恶-6-yl) -2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropene-1,1'-isoproton]-2' _ group Ethyl ketone hydrogen oxalate salt 5',6-dimethoxy snail [cyclopropane-1,3'-iso®bendolin]-1'-imine hydrobromide lc (151mg,0 69mmol) dissolved in 3mL tetrahydrobite, added 2-di-b (8-tert-butyl-4-ethyl-2,3-dihydro-1, 4-benzoxoxazin-6-yl) Ethyl ketone 6b (253 mg, 0.74 mmol) and triethylamine (〇. 2 mL, 1.44 mmol) were stirred for 12 hours. Filtration, the filter cake was washed with hexane (10 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzene And noise 17 Qin_6-φ base)-2-(3'-imino-5',6'-dimethoxy-spiro[cyclopropanone-^,i-isoporphyrin]-2' Ethyl ketone hydrobromide 6 (139 mg, white powder), yield: 35. 9% MS / ESI (ESI): 478 [M+l] 4 NMR (400 MHz, DMSO-form, ppm) : δ 9.68 (Bu.1ΤΪ, s, in) 7.24 (s, 4.4 Hz, 2 Hz, 137 (s, 9. 13(Z?r. s, 1H), 7. 90 (s, 1H), 7.28 ( s, 1H), 1H), 7.08 (s, 1H), 5.16 (s, 2H), 4. 30 (t, j 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.44 (q, j 2H), 3.38 (t, /=4. 4 Hz, 2H), 1.68 (m, 4H)) 95255 101 201242964 9H), 1. 23 (t, / = 7. 2 Hz, 3H) Example 7 1 -(3-tert-butyl-decyloxy-5-morpholinylphenyl)_2_(5,6,-diethoxy-3'-imino-spiro[cyclopropane-1,1,-iso Porphyrin]-2, _yl) ethyl ketone hydrobromide

In the first step, 1,2-dibromo-4,5-diethoxybenzene was dissolved in 200 mL of two-gas methane in an ice bath of '2-diethoxybenzene 7a (16.6 g, 100 mmol). 'Drip addition (i 〇 mL, 200 mmol), and the reaction was stirred at room temperature for 4 hours. i〇〇mL水 and 1 g of sodium sulfite were added to the reaction mixture, and the organic phase was washed with a saturated sodium carbonate solution (15 mL), dried over anhydrous sodium sulfate, and then evaporated. , 2-dibromo-4, 5-diethoxybenzene 7b (29. 8 g, white solid), yield: 92. 〇%. ^ NMR (400 MHz, CDCh, ppm): δ 7. 10 (s, 2Η), 4. 07 (q, /= 7. 2 Hz, 4H), 1.47 (t, J = 1.2 Hz, 6H) Step 4,5-ethoxylated phthalonitrile, 1,2-di--4, 5-ethoxybenzene 7b (13.62 g, 42 mmol) 102 95255 201242964 Dissolved in 150 mL of dimethyl ya Copper bromide (14.97 g, 167.2 mmol) and moth steel (718 g, 37 7 mmol) were added, and the reaction was stirred for 4 hours at i6 °C. The reaction solution was poured into a mixture of 25 mL of concentrated aqueous ammonia and ethyl acetate (v/v = 1:1. 5), and the filter cake was washed with water (1 mL) and ethyl acetate (100 mL×2). The aqueous phase was extracted with ethyl acetate (1 mL). EtOAc (EtOAc m. The pressure was concentrated, and the residue obtained by column chromatography was purified by eluent system β, and 4,5-diethoxy phthalic acid 7c (5 42 g, yielding the title yield: 59. 7 %. Color solid), yield *H NMR (400 MHz, CDCl3, ppm): δ 7. 16 (s 2 / = 4. 1 Hz, 4H), 1.54 (t, / = 4. 1 jj2 ( 2〇( q 〇H) The third step 5,6 - ethoxy snail [cyclopropanone -1,3' _ iso-bow beer], acid salt 1, iminohydroquinone, under ice bath, 4 5-diethoxyphthalonitrile 7e lOmmol) was dissolved in 1 mL of diethyl ether, adding 16 g of citric acid, θ iso-injection, fq 11.2 mmol) and ethyl magnesium bromide (7.3 mL, 21.911111101). 6 .3lnL, should be 2 hours. Add 55 mL·methanol, use a silicone tube to smear the color, and then resolve the residue obtained by purifying the reverse line A to obtain the title product 5, 6, and the eluent of the propane-1,3,-isoporphyrin. ]-i, _imine hydrobromide 7 gas-based snail [ring

Fa (1 〇D yellow powder), yield: 51.2%. · g, orange MS m/z (ESI): 247 [M+l] 4 NMR (400 MHz, DMSO-' ppm): δ i〇di / • s, 1H), 95255 103 201242964 9. 37 (Z? r. s, 1H), 9. 14 (Z?r. s, 1H), 7. 88 (s, 1H), 7.01 (s, 1H), 4.17 (m, 4H), 1.69 (m, 2H), 1.43 (m, 2H), 1.37 (m, 6H) Step 4 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(5',6'-di-B Oxy-3'-imino-spiro[cyclopropane~1,1,-isoindoline]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxy snail [ Cyclopropane-indole, 3,-isoporphyrin]-indole-imine hydrogenate salt 7d (195mg, 〇. 79mmol) was dissolved in 3mL of tetrahydroanthracene 0 in the middle of '2-bromo-1-(3-) tert-Butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (310 mg, 0.84 mmol) and triethylamine (5 mL, 1.08 mmol). Filtration, the filter cake was washed sequentially with n-hexane ( 丨〇 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 1-(3-tert-butyl-4-methyl-5-morpholinylphenyl)-2- (5',6'-diethoxy-3,-imino-spiro[cyclopropane-1,indole-isoindoline]-2'-yl)ethanone hydrobromide 7 (18〇mg , white powder), Yield: 36.9% MS m/z (ESI): 536 [M+l] *H NMR (400 MHz, DMSO-t/e, ppm): 6 9.69 {br. s, 1H ), 9. 13 (br. s, 1H), 7. 91 (s, 1H), 7. 65 (d, / = 2. 0 Hz, 1H), 7.56 (d, /= 2.0 Hz, 1H), 7. 06 (s, 1H), 5. 23(s, 2H), 4.18 (q, /= 7.2 Hz, 2H), 4.12 (q, / = 7. 2 Hz, 2H), 3.97 (s, 3H) , 3.83 (m, 4H), 3.03 (m, 4H), 1.64 -1.61 (m, 4H), 1.41 (m, 15H) Example 8 104 95255 201242964 1-(3-tert-butyl-4-decyloxy -5·-pyrrolidin-1-yl-phenyl)-2-(5',6'-diethoxy_3'-imino-spiro[cyclopropan-1,1'-iso^弓卜多,·-2'-yl) ethyl ketone hydrobromide

The first step of 1-(3-tert-butyl-4-decyloxy-5-nitro-phenyl)ethanone is 1-(3-tert-butyl-4-transyl-5-succinyl-phenyl). Ethyl ketone 5a (11.6 g, 48.9 mmol) was dissolved in 150 mL of acetone, potassium carbonate (16.9 g, 122 mmol) and iododecane (23.2 mL, 372 mmol) were added, and the reaction was stirred at 80 ° C for 12 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified with EtOAc EtOAc (EtOAc) Yield: 72.8%. MS m/z (ESI): 252 [M+l] Step 2 105 95255 201242964 1-(3-Amino-5-tert-butyl-4-methoxyphenyl)acetamidine 1-(3- tert-Butyl-4-decyloxy-5-nitro-phenyl)ethyl _ % (4.8 g, 19 mmol) was dissolved in 50 mL of ethanol and water (V/V = 4.1) wt. Ammonium (4.1 g, 75 mmol) and iron powder (2 i 38 匪ol) were stirred at 80 ° C for 1 hour. Filtration, the filtrate was decompressed and concentrated to 100 mL of water and 100 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous sodium sulfate Filtration, concentration of the filtrate under reduced pressure, and purification of the obtained residue by eluent column chromatography to give the product of 1-(3-amino-5-tert-butyl-4-decyloxyphenyl) Outline (3' title grey solid), yield: 81. 〇%. ' 6 g, MS m/z (ESI): 222 [M+l] Step 3 1-(3-tert-Butyl-4-decyloxy-5-pyrrolidine-p-phenyl-phenyl) 1-(3-Amino-5-tert-butyl-4-yloxyphenyl)ethyl-g, 9.05 mmol) and 1,4-dibromobutane (2 54 g, 1177 curry (2·〇) To 20 mL of hydrazine, hydrazine-dimercaptoguanamine, potassium carbonate (3. ι dissolved 22.63 〇1) and potassium iodide (〇. 15 g, 〇91 mm 〇1) were added, and stirred for 8 hours at 8 Torr. Filtration, the filtrate was concentrated under reduced pressure, and then added with 5 hrs of water, and the mixture was taken to give a mixture of 50% of the mixture, and the organic phase was combined, washed with saturated sodium carbonate solution, and dried (20 mL×3), dried over anhydrous sodium sulfate The residue obtained by purifying the column chromatography with eluent system 6 is used to prepare the product (3-tert-butyl-4-methoxy_5-perylpyroxypyrene-bumpy = stupid = to heading 8c ( 1·1 g, white solid), Yield: 44.2%. B. 95255 106 201242964 MS m/z (ESI): 276 [M+l] Step 4 2-Bromo-1-(3-tert-butyl) 1, 4-methoxy-5-pyrrolidine-fluorenyl-phenyl)ethanone 1-(3-tert-butyl-4-decyloxy-5-«pyrazine~byl-phenyl Ethyl ketone 8c (900mg, 3 .27mmol) was dissolved in 10 mL of acetic acid, and added to the mixture of sulphur salt (1.1 g, 3.43 〇1). Stirring reaction for 12 hours. Concentration under reduced pressure, adding 30 mL of water and 30 mL of ethyl acetate, water The extract was extracted with ethyl acetate (50 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (2 〇mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give crystalljjjjjjjjj Yield: 48.3% MS m/z (ESI): 356 [M+l] Step 5 1-(3-tert-butyl-4-decyloxy-5-pyrrolidin-1-yl - Stupid base)_2_(5,,6, _ 春-ethoxy-imino-spiro [cyclopropene-1,1'-iso. D Dlining]_2, _ group) ethyl ketone hydrobromic acid Salt 5',6'-diethoxyspiro[cyclopropane-1,3,-isoporphyrin]-γ _ imine hydrobromide 7d (250mg, 1. 02mmol) was dissolved in 4raL tetrahydroanthraquinone In the middle, 2-bromo-1-(3-tert-butyl-4-decyloxy-5-pyrrolidin-1-yl-phenyl)ethanone 8d (360 mg, 1.02 mmol) and triethylamine (〇) .2mL, 1. 44mmol) The reaction was stirred for 12 hours. The filtered filter cake was washed with n-hexane (10 mL×2) and water (10 mL×3) and then dried in vacuo to give the title product 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl- Phenyl)-2-(5,6,-107 95255 201242964 Diethoxy-3'-imino-spiro[cyclopropane", 卜异啊琳卜2, _ Fu) Ethyl ketone hydrobromide Salt 8 (232 mg, white powder), yield: 38%. Soil MS m/z (ESI): 520 [M+l] 'H NMR (400 MHz, DMSO-c/6&gt; ppm): δ 9.65 {br s 1H) 9.08 (br. s, 1H), 7.88 (s , 1H), 7.77 (b, / = 2. 0 ^ 1H), 7.41 (b, /= 2.0 Hz, lH), 7.05 (s, lH), 5.19 2H), 4.17 (q, /= 7.2 Hz, 2H ), 4.11 (q, / = 7 2 Hz, 2H), 3.66 (s, 3H), 3.10 (m, 4H), ι·93 (m, 4H), 1.74-1.60 (m, 4H), 1.39 (m , 15H) Example 9 1-(3-tert-Butyl-4-decyloxy-5-morpholinylphenyl)_2_(7-imino-2,5-dimethyl-5-phenyl-pyrrole And [3, 4-anthracene-6-yl) ethyl ketone hydrobromide

In the first step 1-(6-methyl-3-«bipyridine)-1-phenyl-ethanol dry ice-acetone bath, 5-bromo-2-methyl-pyridine 9a (172 g lOminol) was dissolved in 10 mL To a solution of diethyl ether (4 4 乩 95255 108 201242964 llmmol) in n-hexane was added dropwise to diethyl ether, and the mixture was stirred for 1 hour, and then acetophenone (1.29 mL, llmmol) was added, and the reaction was further stirred for one hour. To the reaction mixture was added lOraL saturated ammonium sulfate solution, the aqueous phase was extracted with ethyl acetate (2 mL mL), and the organic phase was combined, washed with saturated sodium carbonate solution (1 〇mL×3), dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure, the residue obtained was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc , yellow solid), yield: 84.5%. MS ra/z (ESI): 214 [M+l] NMR (400 MHz, CDCla, ppm): δ 8. 55 (s, 1H), 7. 65 (d, / = 8. 4 Hz, 1H) , 7.35 (m, 5H), 7.11 (d, / = 8. 4 Hz, 1H), 2.56 (s, 3H), 1.98 (s, 3H) Step 2 5-(1-azido-1-phenyl) -ethyl)-2-methyl-n-pyridinium under ice-"1-(6-fluorenyl-3-pyridine)-l-phenyl-ethanol 9b (1.75 g, 8.2 mmol) and sodium azide D.6g, 24.6mmol) was dissolved in _1 Torr of water, 9 mL of concentrated hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. To the reaction mixture, 200 mL of a saturated sodium hydrogencarbonate solution was added to adjust the pH to 7 to 8 and extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with saturated sodium carbonate solution (20 mL×3), dried over anhydrous sodium sulfate 3%。 The title product was obtained in the title compound: 5---------- - - - - - - - - - - - - - - - - - - - - - MS m/z (ESI): 239 [M+l] Η NMR (400 MHz, CDCh, ppm): δ 8. 53 (s, 1H), 7. 57 (d /= 8.0 Hz, 1H), 7.37 (m, 5H), 7.16 (d, / = 8. 〇Hz 95255 109 201242964 1H), 2.62 (s, 3H), 2.07 (s, 3H) Step 3 5-(1-stack-i-phenyl -ethyl)_2_methyl_D than the bite i_oxide 5-(1-azido-1-phenyl-ethyl)_2_ fluorenyl quinone 9c (1. 8 g, 7. 6 mmol) was dissolved in 30 mL of dichloromethane, and m-chloroperoxybenzoic acid (2·δ g' 15·lmmol) was added, and the reaction was stirred for 12 hours. Add 20 mL of dioxane to the reaction solution, wash with saturated sodium bicarbonate solution (3 〇mL×3), extract the aqueous phase with ethyl acetate (50 mL×3), combine the organic phase, and wash with saturated sodium carbonate solution (20 mL×3) Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The obtained residue was purified by eluent column chromatography with eluent system B to give the title product 5-(1_~~~~~~~~~~~~~~~~~ 0%。 2-曱- η υ 1 1 1 1 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 !H NMR (400 MHz, CDCh, ppm): δ 8. 31 (s, 1H), 7. 36 (m, 7H), 2.58 (s, 3H), 2.04 (s, 3H) Step 4 - ( 1-azido-1-phenyl-ethyl)-6-methyl-indolepyridine-2-carbonitrile 5-(1-azido-1-phenyl-ethyl)-2-methyl- α 咬 咬 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 〇mL, 7. 7mmol), and the reaction was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -2-Nitrile 9e (1.6 g, pale yellow oil) crude. MS m/z (ESI): 264 [M+l] 95255 110 201242964 H NMR (400 MHz, CDCh, ppm): δ 8.04 (d, / = 8. 4 jjz 1H), 7.47 (m, 6H), 2.63 (s, 3H), 2.28 (s, 3H) The fifth step 2,5--mercapto-5-phenyl-6 and -indolebi[3,4-Z?] than the bite imine will be 3- (1-Azepine-1-phenyl-ethyl)-β-mercapto-π ratio bite_2_nitrile % (1. 68 g, 6.39 mmol) was dissolved in 35 mL of tetrahydrofuran, water and triphenyl group were added. Phosphine (3.35 g, 12.8 mmol) was scrambled for 12 hours. The reaction mixture was concentrated under reduced pressure and purified tolud</li></RTI></RTI> eluted with eluent system A to give the title product 2, 5-dimethyl-5-phenyl-6 and - pirox [3, 4 1%。 pyridine-7-imine 9f (0.44 g, pale yellow solid), yield: 29. 1%. MS m/z (ESI): 238 [M+l] 丽 R (400 MHz, CDC13, ppm): δ 7. 91 (d, 7.6 Hz 1H), 7.50 (d, /= 7.6 Hz, 1H), 7 .17(m,5H), 6.61(s' 2H), 2.55 (s, 3H), 1.69 (s, 3H) ' The sixth step per 1 -(3-tert-butyl-4-decyloxy-5-吓 · phenyl)-2-(7'imino- 2 dimethylamino-5-phenylpyrolo[3,4-Z?]pyridin-6-yl)ethanone hydrogen oxalate 2 , 5-dimethyl-5-phenylpyrazine [3, 4-do] π ratio bite_7_imine 9f (237 mg, 1 mmol) and 2-bromo-1-(3-tert-butyl, 4 -Methoxymorpholine phenyl)ethanone 2h (444 mg, 1.2 mmol) was dissolved in 3 x-N-dimethylamine, and the reaction was stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified with eluent system A to give 95255 111 201242964 title product 1-(3-tert-butyl-4-decyloxy-5-carbinylphenyl)_2 (ethylidene ketone) 5-8%indolyl-5-phenyl-β 〇 〇 [3, 4-6] ntb bit-6-yl) hydrobromide 9 (120 mg, pale yellow solid), yield: 19.8% . MS m/z (ESI): 527 [M+l] 4 MR (400 MHz, DMSO-忒, ppm): δ 7.97 (d / = ο λ , 〇 Hz 1H), 7. 68 (d, /= 8 . 0 Hz,1H), 7·52 (s,1H),7 47 ( 1H), 7. 38 (m,5H), 5. 50 (d,/= 18. 8 Hz, 1H), 5 l6 ( d 18. 8 Hz, 1H), 4. 03 (s, 3H), 3. 80 (m, 4H), 2 98 ( 4H), 2.74 (s, 3H), 1.99 (s, 3H), 1.33 (s , 9H) Example 10 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6,-diethoxy~3, _imino-spiro[cyclopropane] -1,1'-isoporphyrin]-2,-yl)ethanone hydrobromide

The first step is 1-(3,5~-sutrabutyl-4-carbylphenyl)-2-(5',6'-diethoxy-3, a one-fee-based snail [cyclopropanone- 1 , 1' _iso^ 引 n朵淋]_2'-yl) ethyl ketone hydrogen oxalate salt 5',6'-diethoxyspiro[cyclopropane-1,3,-isoporphyrin]-1 , an imine shoulder acid salt 7d (247mg, lmraol) was dissolved in 4mL tetrahydrofuran, added 2-&gt; odorous 1-1-(3, 5-di-tert-butyl-4-hydroxyphenyl) ethyl ketone If (393 mg, 112 95255 201242964 1. 27 mmol) and triethylamine (15 mL, 1.08 mmol), the reaction was stirred for 12 hours. Filtration of the 'filter cake sequentially with n-hexane (10 mL x 2) and water (10 mL x 3 ), dried in vacuo to give the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5',6 '-Diethoxy-3'-imino-spiro[cyclopropane-1,1,-isoindolyl]-2'-yl)ethanone hydrobromide salt 1 〇 (233 mg, white powder), Yield: 41.8%. MS m/z (ESI): 493 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 9.65 {br. s, 1H), # 9. 10(Z?r. s , 1H), 8. 06(Z?r. s, 1H), 7. 91 (s, 1H), 7.85 (s, 2H), 7.06 (s, 1H), 5.30 (s, 2H), 4.18 (q , / = 7. 2 Hz, 2H), 4. 11 (q, /= 7. 2 Hz, 2H), 1. 76 -1. 66 (m, 2H), 1.35 (m, 24H) Example 11 1 -(3-tert-butyl-5-diethylamino-4-methoxyphenyl)-2-(5,6,-diethoxy-imido-snail [cyclopropane-1, 1'-iso-π-u-u-lin]- 2'-yl)ethanone hydrobromide

The first step is 1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)ethanone 95255 113 201242964 卜(3-Amino-5-tert-butylmethoxyphenyl) B Ketone 8b (9. 8 g, 44_1) was dissolved in 50 mL of N,N-dimethylmethamine, and potassium carbonate (18.35, 133111111〇1) and Ethylene (2〇.72,133111111〇1) were added. The reaction was stirred for 12 hours. Add 1 〇〇 of this water to the reaction solution, and extract with ethyl ether (50 mL ♦ _ _ _ Lai and Qi Xian transfer money (2GmLx3), anhydrous sulfuric acid, dry, filtered, concentrated under reduced pressure, with (four) column chromatography to wash The resulting residue was purified to give the title product (3-tert-butyl-5-ethylamino-4-methoxyphenyl)ethanone lll (2. 4 g, yellow oil). Yield: 19.5%. MS m/z (ESI): 278 [M+l] Step 2 2-bromo-1-(3-tert-butyl-5-diethylamino-4-methoxy Phenyl)ethanone 1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)ethanone iia (2.4 g, 8.66 mmol) was dissolved in 10 mL of acetic acid and added to the mixture. The mixture was stirred for 12 hours, concentrated under reduced pressure, added with 20 mL of water, extracted with ethyl acetate (50 mL×3), combined organic phase, washed with saturated sodium carbonate solution (20 mL×3), dried over anhydrous sodium sulfate, EtOAc (EtOAc)EtOAc. 5-diethylamino-4-methoxyphenyl)ethanone lib (850 mg, yellow solid), yield : 27. 5% MS m/z (ESI): 358 [M+l]]H NMR (400 MHz, CDCh, ppm): δ 7. 67 (m, 1H), 7. 56 (m, 1H) , 4.46 (s, 2H), 3.96 (s, 3H), 3.21 (m, 4H), 1.45 (s, 9H), 1.11 (m, 6H) 114 95255 201242964 Third Step 1 - (3-tert-Butyl- 5-diethylamino-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropan-1,1'-isoindole N-line]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-1' imine hydrobromide The acid salt 7d (246 mg, 1 mmol) was dissolved in 5 mL of tetrahydrofuran, and 2-bromo-1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)ethanone lib ( 368 mg, 1.03 mmol) and triethylamine (〇.l5 mL, 1.08 mmol), were spoiled for 12 hours. After filtration, the cake was washed with tetrahydrofuran (imL), n-hexane (10 mL×2) and water ( 10 mL x 3), dried in vacuo to give the title product 1-(3-tert-butyl-5-diethylamino-4-methoxyphenyl)-2-(5',6'-diethoxy-3' -Imino-spiro [cyclopropane-1, 1'-iso-n-bendolin]-2'-yl) ethyl ketone hydrobromide 11 (314 mg, white powder), produced Rate: 52.2%. MS m/z (ESI): 523 [M+l], NMR (400 MHz, DMSO-c/g, ppm): δ 9.69 {br. s, 1H), _ 9.15 (Ζλτ. s, 1H), 7.93 (s,1H), 7.59 (d,7&quot;= 1.6 Hz, 1H), 7.54 (d, /= 1.6 Hz, 1H), 7.06 (s, 1H), 5.20 (s, 2H), 4.18 (q, / = 7. 2 Hz, 2H), 4.12 (q, / = 7. 2 Hz, 2H), 3. 88 (s, 3H), 3. 17 (q, /= 7. 2 Hz, 4H), 1 76 -1. 61 (m, 4H), 1.40 (m, 15H), 1.20 (t, / = 7. 2 Hz, 6H) Example 12 1~[3-tert-butyl-4-methoxy- 5-(1-Benbityl)phenyl]- 2-(5',6,-diethoxy-3'-imino-spiro[cyclopropan-1,1,-isoindole] -2, _yl) ethyl ketone hydrobromide 115 95255 201242964

First step l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]ethanone 1-(3-amino-5-tert-butyl-4-methoxy Ethyl phenyl) ethyl ketone 8b (2.21g, 1 〇 curry 1) and hydrazine, 5_ dibromopentane (4 6 g, 2 〇 mm 〇 1) dissolved in 20 mL of N,N-dimercaptocarboxamide Add potassium carbonate (4.14 g, 3〇mm〇1) and potassium iodide (〇.17g, 1. Ommol), 5 (TC stirring reaction for 12 hours. Add 20 mL of water to the reaction solution, and extract with diethyl ether (5 〇mLx3), the organic phase was combined, washed with saturated sodium sulphate solution (2 〇mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B. The title product 1-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]ethanone 12a (1.8 g, m.p.). z (ESI): 290 [M+l] *H NMR (400 MHz, CDCh, ppm): δ 7. 66 (d, /= 2.0 Hz, 1H), 7-55 (d, /= 2.0 Hz, 1H ), 4.03 (s, 3H), 3.03 (m, 4H), 2. 60(s, 3H), 1.79(ra, 4H), 1.62 (m, 2H), 1.45 (s, 9H) Step 2 Bromo-l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]ethanone 1-[3-tert-butyl-4-methyl _5_(1-piperidinyl)phenyl]ethanone 116 95255 201242964 12a (1.8 g, 6.2 mmol) dissolved in 2 mL of acetic acid, added tribromopyridine rust salt (2.99 g, 7 15 mmol), stirring for 12 hours. Concentration under reduced pressure, EtOAc (EtOAc) (EtOAc (EtOAc) Concentration by pressure, the residue obtained was purified by eluent column chromatography using eluent system B to give the title product 2-di-l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl) Phenyl]ethanone 12b (850 mg, yellow solid), yield: 37. 3%. MS m/z (ESI): 370 [M+l] NMR (400 MHz, CDCh, ppm): δ 7.68 (d, /= 2. 0 Hz, 1H), 7.58 (d, /= 2.0 Hz, 1H), 4.54 (s, 2H), 4.04 (s, 3H), 3.03 (ra, 4H), 1.80 (m, 4H), 1.66 (m, 2H), 1.47 (s, 9H) The third step l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]_2-(5) ,, 6'-di-φ-ethoxy-3,imido-spiro[cyclopropane-1,1'-isoindole]_2, _yl)ethanone hydrobromide 5,6 - Ethoxy snail [cyclopropanone-1,3'-iso-sigma 丨 朵 朵 琳]_1, an imine hydrobromide 7d (247mg, 1mmol) was dissolved in 5mL of tetrahydrofuran, and added 2-di-b [3-tert-butyl-4-decyloxy-5, (bottom) benzene Ethylketone 12b (424 mg, 1.15 face 1) and triethylamine (〇2 mL, 144 〇1) were stirred for 12 hours. After the meal, the cake was sequentially dried in vacuum (5mLx2) and water (5mLx2), and dried under vacuum to obtain the title product [3_tert-butyl+95255 117 201242964 base-spiro[cyclopropan-1,1,-吲哚]] 2'-yl) ethyl ketone hydroquinone hydrazine 12 (246 mg, white powder), yield: 39. 90 / 〇. MS m/z (ESI): 523 [M+l] *H NMR (400 MHz, dUSO-ώ, ppm): δ 9.70 {br. s, 1H) 9. 13 {br. s, 1H), 7. 93 (s, 1H), 7. 62 (d, / = i. 8 Hz&gt; 1H), 7.56 (d, /= 1.8 Hz, 1H), 7.06 (s, 1H), 5.22 (s 2H), 4.18 ( q, /= 7. 2 Hz, 2H), 4. 12 (q, 7 2 Hz, 2H), 3.97 (s, 3H), 2.98 (m, 4H), 1.74 (m, 6H), I.57 ( m, 4H), 1.39 (m, 15H) Example 13 N-[3-tert-butyl-5-[2-(5',6,-diethoxy-3'-imino-spiro[ring] Propylene-1,1-iso 0 bowbendolin]-2'-yl)ethinyl]-2-methoxyphenyl]acetamidamine hydrobromide

The first step of N-(5-ethenyl-tert-butyl-2-methoxyphenyl)acetamide is 1-(3-amino-5-tert-butyl-4-oxo-oxygen) in an ice bath Ethyl phenyl) ketone 8b (12.0 g, 54 mmol) was dissolved in 100 mL of tetrahydrofuran, triethylamine (15 mL, 109 mmol) was added, and the reaction was stirred for 0.5 hr. (6. 14 mL, 81 mmol), stirring was continued for 2 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) 4 g, white solid), yield: 94. 4%. MS m/z (ESI): 264 [M+l] _ !H NMR (400 MHz, CDCh, ppm): δ 8.54 (d, / = 2. 0 Hz, 1H), 7.71 (d, /= 2.0 Hz , 1H), 7.38 {br. s, 1H), 3.74 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H), 1.33 (s, 9H) Step 2 N-[5-(2 -Bromoethendyl)-3-tert-butyl-2-methoxyphenyl]acetamidamine N-(5-ethenyl-3-tert-butyl-2-methoxyphenyl) acetamidine The amine 13a (3.7 g, 14. lmmol) was dissolved in 20 mL of acetic acid, and then tribromopyridinium φ salt (4.5 g, 14.1 mmol) was added, and the reaction was stirred for 12 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) Column chromatography to purify the residue obtained in eluent B to give the title product N-[5-(2-bromoethyl)-3-tert-butyl-2-methoxyphenyl]acetamide 13b ( 3.2%, white solid), yield: 66. 0%. !H NMR (400 MHz, CDCh, ppm): δ 8.68 (d, / = 2. 0 Hz, 1H), 7.85 (d, /= 2.0 Hz, 1H), 7.30 (br. s, 1H), 4.48 119 95255 201242964 (s, 2H), 3.86 (s, 3H), 2.31 (s, 3H), 1.43 (s, 9H) The third step N-[3-tert-butyl-5-[2-(5',6 '-Diethoxy-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-2-methoxyphenyl]acetamidine Amine hydrobromide dissolves 5',6'-diethoxyspiro[cyclopropane-1,3'-isoindoline]-1,-imine hydrogen oxalate 7d (243 mg, 〇·99 mmol) Add N-[5-(2-bromoethenyl)-3-tert-butyl-2-decyloxyphenyl]acetamide 13b (395 mg, 1.15 mmol) and triethylbenzene in 5 mL of tetrahydrofuran. The amine (〇.l5 mL, 1.08 mmol) was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×3) and dried in vacuo to give the title product N-[3-tert-butyl-5-[2-(5',6'-diethoxy- 3'-Imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-2-methoxyphenyl]acetamide hydrobromide 13 ( 2重量。 193mg, white powder), yield: 33.2%. MS m/z (ESI): 508 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 9.76 {br. s, 1H), 9. 68 (Z?r. s, 1H), 9. 18 (Z?r. s, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7. 73(s, 1H), 7. 06 (s, 1H), 5. 18 (s, 2H), 4.18 (q, /= 7.2 Hz, 2H), 4.16 (q, / = 7. 2 Hz, 2H), 3.80 (s, 3H), 2.15 (s, 3H), 1.74 -1.60 (m, 4H), 1.39 (m, 15H) Example 14 2-[ [3-tert-butyl-5-[2-(5',6'-diethoxy-3'-imido- snail [cyclopropane-1, fluorene-isoporphyrin]-2'-yl)ethinyl]-2-indolyl]amino] 120 95255 201242964 base] acetonitrile hydrobromide

The first step 2-[(5-ethylindenyl-3-tert-butyl-2-yloxyphenyl)amino]acetonitrile will be 1-(3-amino-5~t-butyl-4-inoxane Ethyl phenyl) ethyl ketone 8b (I 4.4 g, 65.2 mmol) was dissolved in 100 mL of n,N-dimercaptocarbamide, and potassium carbonate (9.9 g, 72 mmol) and bromoacetonitrile (26.4 g, 220 mmol), 7 The reaction was stirred at 〇 ° C for 12 hours. Filtration and concentration of the filtrate under reduced pressure, adding 3 mL of water, extracting with diethyl ether (20 〇mL×3), combining the organic phases, washing with saturated sodium carbonate solution (5 〇mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAc (EtOAc) elut elut 0%。 Acetonitrile 14a (15. 3 g, yellow solid), yield: 88.0%. MS m/z (ESI): 261 [M+1] R Surface R (400 MHz, CDCI3, ppm): δ 7.56 (d, /= 2.0 Hz, 1H), 7. 30 (d, / = 2. 0 Hz, 1H), 4. 49(Z?r. s, 1H), 4.24 /= 6.8 Hz, 2H), 3.82 (s, 3H), 2.62 (s, 3H), 1.45 (s, 9H) 95255 121 201242964 The second step 2_[[5-(2~bromoethyl)-3-tert-butyl-2-decyloxyphenyl]amino]acetonitrile will be 2-[(5-ethylindenyl-3-tert-butyl) Ethyl-2-oxophenyl)amino]acetonitrile 14a (14. 24 g, 54.7 mmol) was dissolved in 8 mL of acetic acid, and tribromopyridine rust salt (18.37 g, 57.4 mmol) was added. The reaction was stirred for 24 hours. After adding 300 mL of water to the reaction mixture, the aqueous phase was extracted with ethyl acetate (2 mL mL), and the organic phase was combined, washed with saturated sodium sulfate solution (5 〇mL×3), dried over anhydrous sodium sulfate The residue obtained was purified by eluent column chromatography using eluent column chromatography to afford the title product 2-[[5-(2-bromoethyl)-3-tert-butyl-2-methoxyphenyl]amine 0%。 Acetonitrile 14b (126 g, yellow oil), yield: 7. 0%. MS m/z (ESI): 339 [M+l] Step 3 2-[[3-tert-butyl-5-[2-(5',6'-diethoxy_3,-imino) -spiro[cyclopropane-1,1'-isoporphyrin]-2'-yl)ethenyl]-2-methoxyphenyl]amino]acetonitrile hydrobromide 5,6-ethoxy Base snail [Lymphastane-1,3-iso-α cited ο多lin]-imine hydrobromide 7d (249mg, 1. 〇3mmol) was dissolved in 5mL tetrahydrofuran, adding 2-[[5_( 2-bromoethendyl)-3-tert-butyl-2-oxophenyl]amino]acetonitrile 14b (408 mg, 1.19 mmol) and triethylamine (〇.i5 mL, 1.08 mmol), mixed Reaction for 12 hours. Filtration, the filter cake was washed successively with hexane (5 mL×2) and water (10 mL×3) and dried in vacuo to give the title product 2-[[3-(4-butyl-5-[2-[ -3' ~Imino-Spirulina [Cyclopropanone-1, Γ-iso-° 引 °多琳]-2'-yl)ethinyl]-2-methoxyphenyl]amine 122 95255 201242964 base] Acetonitrile hydrobromide 14 (262 mg, white powder), yield: 43.6 / 〇. MS m/z (ESI): 504 [M+l] R R (400 MHz, MSO-also, ppm): δ 9.66 (Z?r. s,1H), 9.17 (br. s, 1H), 7.87 (s, 1H), 7.43 (d, /= 1.6 Hz, 1H), 7. 36 (d, /= 1. 6 Hz, 1H), 7. 07 (s, 1H), 6. 16 (t, / = 6.8 Hz, 1H), 5.20 (s, 2H), 4.40 (d, / = 6. 8 Hz, 2H), 4.18 (q, / = 7. 2 Hz, 2H), 4.11 (q, J= Ί. 2 Hz, 2H), 3.74 (s, 3H), 1.73 -1.62 (m, 4H), 1.40 (m, 15H) • Example 15 1-(8-tert-butyl-4-ethyl-2, 3- Dihydro-1,4-benzo-oxo-Qin-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1,1'- Isoporphyrin]-2'-yl)ethanone argonate

The first step is 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4-benzox-oxo-6-yl)-2-(5',6'-di Ethoxy-3'-imino-spiro[cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxy snail [ Cyclopropane-1,3'-isoporphyrin]-indole-imine hydrobromide 7d (250mg, 1.02mmol) was dissolved in 5mL of tetrahydrofuran 123 95255 201242964, added 2-di-1- 8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzoxoxan-6-yl)-ethanone 6b (408 mg, 1.19 mmol) and triethylamine (〇. I5mL, 1. 08 ol), stir the reaction for 12 hours. Filtration, the filter cake was washed with hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2, 3-dihydro-1,4-benzene And "oxazol-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane_丨, hydrazine, monoisoporphyrin]-2' - Ethyl ketone hydrobromide 15 (224 mg, white powder), yield: 37.6%. MS m/z (ESI): 506 [M+l] H NMR (400 MHz, DMSO-i/e, ppm): δ 9·7 〇 (/?/· s 1H) 9. 14 (Z?r. s, 1H), 7. 89 (s, 1H), 7.27 (m, 2H), 7. 04 (s, 1H), 5. 16 (s, 2H), 4. 29 (t, / = 4. 4 Hz, 2H), 4. 17 (q, /= 7. 2 Hz, 2H), 4.11 (q&gt; / = 7. 2 Hz, 2H), 3.10 (m, 4H), 1. 75 (m, 4H) , 1. 36 (m, 15H), 1. 19 (t, /= 7. 2 Hz, 3H) Example 16 2-[8-tert-butyl-6-[2-(5',6,-di Ethoxy-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethenyl]-2,3-dihydro-1,4-benzo[0] Oxazin-4-yl]acetonitrile hydrobromide 124 95255 201242964

First Step 2-(6-Ethyl-8-tert-butyl-2,3-dihydro-1,4-benzo-βoxan-4-yl)_ φ Acetonitrile 1-(8-tert-butyl) Base-3,4-dihydro-2 and -1,4-benzoxanthene-yl) Ethylketone 5c (12 g, 51.4 mmol) was dissolved in 60 mL of N,N-dimercaptocarboxamide Cesium carbonate (7.82 g, 56.6 mmol) and bromoacetonitrile (12.33 g, 103 mmol) were stirred at 70 ° C for 4 hours. To the reaction mixture, 2 mL of water was added, and the mixture was extracted with diethyl ether (200 mL×3). The organic phase was combined, washed with saturated sodium chloride (50 mL×3), dried over anhydrous sodium sulfate and filtered. The residue obtained by column chromatography was purified by eluent system B to give the title product: 2-(6-ethylhydrazino-8-tert-butyl-2, 3-dihydro-1, stupid and biting «»桊_4 -yl)acetonitrile 16a (9.4 g, white solid), yield: 67. MS m/z (ESI): 273 [M+l] *H NMR (400 MHz, CDCla, ppm): δ 7. 52 (d, /=2 0 Hz 1H), 7.33 (d, /=2.0 Hz, 1H), 4.44 (m, 2H), 4.29 (s 2H), 3.45 (m, 2H), 2.60 (s, 3H), 1.43 (s, 9H) Step 2 2-[6-(2-Bromoacetamidine) Base)-8-tert-butyl-2,3-dihydro-1,4__benzoindole. Qin 95255 125 201242964 -4-yl]acetonitrile 2_(6-ethenyl-8-tert-butyl-2,3-dihydro-1,4-benzo-p-methyl-4-yl)acetonitrile 16a (9 38 g, 34. 4 mmol) was dissolved in 80 mL of acetic acid, tribromopyridinium salt (11 g, 34.4 mmol) was added, and the reaction was stirred for 24 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with diethyl ether (1 mL mL). The organic phase was combined, washed with saturated sodium carbonate solution (50 mL×3), dried over anhydrous sodium sulfate, filtered and filtered. Chromatography The residue obtained was purified using eluent B to give the title product 2-[6-(2-bromoethyl)-8-tert-butyl-2, 3-dihydro-1,4-benzene.乙-4-基] acetonitrile 16b (3.0 g, black solid), yield: 24.6%. !H NMR (400 MHz, CDCh, ppm): δ 7.57 (d, / = 2. 0 Hz, 1H), 7.36 (d, /= 2.0 Hz, 1H), 4.47 (m, 2H), 4.43 (s, 2H), 4.29 (s, 2H), 3.47 (m, 2H), 1.43 (s, 9H) Step 3 2-[8-tert-Butyl-6-[2-(5',6'-diethoxy -3'-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethenyl]-2,3-dihydro-1,4-benzoxazine -4-yl]acetonitrile hydrobromide salt 5',6'-diethoxyspiro[cyclopropane-1,3,-isoindoline]-1,-imine hydrobromide 7d (257 mg, 1·04 mmol) dissolved in 5 mL of tetrahydrofuran 'Addition of 2-[6-(2-bromoethenyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxoxoxan-4 -Based] Acetonitrile 16b (458 mg, 1.30 mmol) and triethylamine (〇·15 mL, 1. 〇8nmol) were stirred for 12 hours. Filtration, the filter cake was washed with hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product 2-[8-tert-butyl-6-[2-(5,,6,-diethoxy- 3,-imino-spiro 126 95255 201242964 [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethinyl]-2,3-dihydro-1,4-benzoxazine 4-8%] acetonitrile hydrobromide 16 (317 mg, yellow powder), yield: 50.8%. MS m/z (ESI): 517 [M+l]^ NMR (400 MHz, DMSO-form, ppm): δ 9.67 Ur·s, 1H), 9. 17 (Z?r. s, 1H), 7.89 (s, 1H), 7. 48 (s, 1H), 7.45 (s, 1H), 7. 07 (s, 1H), 5.19 (s, 2H), 4.72 (s, 2H), 4.42 (m, 2H) ), 4.18 (q, / = 7. 2 Hz, 2H), 4.11 (q, / = 7. 2 Hz, # 2H), 3.40 (m, 2H), 1.75 - 1.62 (m, 4H), 1.38 (m , 15H) Example 17 [3-(1-adamantyl)-4-decyloxy-5-morpholinylphenyl]-2-(5',6'-diethoxy-3'-Asia Amino-spiro[cyclopropan-1,1'-isosigma π 吓 ·]-2'-yl)ethanone oxime bromide

The first step 1-[3-(bumantyl)-4-hydroxyphenyl]ethanone 127 95255 201242964 1-(4-Pyridylphenyl)ethyls 17a (408 mg, 3 mmol) and diamond powder-1 - Alcohol 17b (456 mg, 3 mmol) was dissolved in 2 mL of dioxane, concentrated sulfuric acid (0.16 mL, 3 minol) was added and stirred at room temperature for 12 hours. The reaction solution was poured into 10 mL of water, and 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and extracted with a solution of dichlorohydrazine (15 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) %. MS m/z (ESI): 271 [M+l] NMR (400 MHz, CDCh, ppm): δ 7.94 (d, / = 2. 0 Hz, 1H), 7. 75 (dd, /y = 8. 4 Hz, = 2. 0 Hz, 1H), 6. 76 (d, /= 8. 4 Hz, 1H), 6. 00 (s, 1H), 2. 60 (s, 3H), 2. 24 ( s, 9H), 1.83 (s, 6H) The second step l-[3-(1-adamantyl)-4-carbyl-5-anthracene-phenyl]ethanone 1-[3-(1- Adamantyl)-4-hydroxyphenyl]ethanone i7c (435 mg, 1.61111111〇1) is dissolved in 111111^acetonitrile and 1^,1'1-didecylguanamine (^/'^ = 9:2) N-iodobutanediamine (398. 4 mg, 1.77 mmol) was added to the mixed solvent, and the reaction was stirred for 0.5 hour. The residue was purified by EtOAc (EtOAc) elut elut (300 mg, white solid), Yield: 47.0%. MS m/z (ESI): 395 [Ml] NMR (400 MHz, CDCh, ppm): δ 8.20 (d, /= 2.0 Hz, 128 95255 201242964 1H), 7.89 (d, 2.0 Hz, 1H), 6.02 ( s, lH), 2. 58 (s, 3H), 2. 15 (s, 9H), 1.82 (s, 6H) The third step l-[3-(l-金刚烧基)-5_峨_4 _Methoxy phenyl] ethyl ketone 1-(3-(l-adamantyl)-4-hydroxy-5-iodo-phenyl]-ethanone 17d (303 mg, 0.77 mmol) was dissolved in 15 mL of acetone and added Potassium carbonate (316.8 mg, 2.3 mra 〇l) and methyl iodide (0.12 mL, l 91 mm 〇l) were stirred for 12 hours. Filtration, the filter cake was washed with ethyl acetate (1 〇 mL×2), filtrate was concentrated under reduced pressure, and ethyl acetate (20 mL) was added. The organic phase was combined and washed with water (20 mL×3) and saturated sodium carbonate solution (2 mL) The sodium sulphate was dried over; the solution was concentrated under reduced pressure to give the crude product of the title product, ss. MS m/z (ESI): 411 [M+l] *H NMR (400 MHz, CDCh, ppm): δ 8.30 (d, / = 2. 4 Hz, _ 1H), 7.96 (d, /= 2. 4 Hz, 1H), 3.98 (s, 3H), 2.60 (s, 3H), 2.09 (s, 9H), l. 82 (s, 6H) The fourth step l-[5-(l, 1--A Ethyloxy)-3-indol-2-methoxyphenyl]ashamcinal 1-[3-(1-adamantyl)-5-iodo-4-indolyl]ethanone i7e ( 123mg, 0. 3mmol) was dissolved in 2mL of decyl alcohol, adding tridecyl ortho-decanoate (95. 5mg, 0.9mmol) and camphorsulfonic acid (3 48mg, 〇〇15mm〇1), stirring reaction 3 at 6〇°〇 hour. Add 2 mg of potassium carbonate and 2 mL of water, extract with ethyl acetate (10 mL×3), combine the organic phases, and wash with saturated potassium carbonate solution 129 95255 201242964 (10 mL×3) and saturated sodium chloride solution (i〇mLx2) Drying with 'anhydrous sodium sulfate' to give the title product 1-[5-(1,b-dimethoxyethyl)-3-iodo-2-nonyloxyphenyl]adamantane 17f (135 mg, yellow oil) The yield was 98.7%. !H NMR (400 MHz, CDCh, ppm): δ 7.85 (d, / = 2. 0 Hz, 1H), 7.41 (d, /= 2.0 Hz, 1H), 3.93 (s, 3H), 3.21 (s, 6H), 2.11 (s, 9H), 1.81 (s, 6H), 1.54 (s, 3H) Step 5 [3-(1-Adamantyl)-4-methoxy-5-morpholinylphenyl Ethyl ketone was dissolved in [25-(1,1-dimethoxyethyl)-3-iodo-2-methoxyphenyl]adamantane 17f (123 mg, 0.3 mmol) in 20 mL of toluene. Morpholine (1.74 g, 20 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (196.8 mg, 0.5 mmol), tris(dibenzylideneacetone) were added in that order. Palladium (228. 9 mg, 0.25 mmol) and sodium butoxide (1.92 g, 20 mmol) were stirred at 90 °C for 3 hours. Filtration of the 'cakes with ethyl acetate S (10 mL×3), the filtrate was concentrated under reduced pressure, 5 mL of acetic acid was added, stirred for 1 hour, concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent column chromatography. The title product 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]ethanone 17 g (560 mg, yellow solid). *H NMR (400 MHz, CDCh, ppm): δ 7.61 (d, / = 2. 0 Hz, 1H), 7.49 (d, /= 2.0 Hz, 1H), 3.99 (s, 3H), 3.89 (m, 4H), 3.08 (m, 4H), 2.57 (s, 3H), 2.09 (s, 9H), 1.79 (s, 6H) Step 6 130 95255 201242964 l-[3-(l-Adamantyl)-4 -methoxy_5-morpholinylphenyl]-2-bromo-ethanone [3-(1-adamantyl)~4-decyloxy-5-morpholinylphenyl]ethanone 17g (527mg , 1.42 mmol) was dissolved in 8 mL of acetic acid 'added to the triad 0 to bite the salt (455 mg, 1.42 mmol)' and stirred for 3.5 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained by purifying the solvent B was obtained to give the title product 1-[3-(1-adamantyl)-4-decyloxy-5-morpholine-phenyl]-2-bromo-ethanone 17h (230 mg, Yellow solid), yield: 36.0%. NMR NMR (400 MHz, CDCh, ppm): δ 7.65 (d, / = 2. 4 Hz, 1H), 7.53 (d, /= 2. 4 Hz, 1H), 4.42 (s, 2H), 4. 01 (s, 3H), 3.90 (m, 4H), 3.09 (m, 4H), 2.09 (s, 9H), 1.79 (s, 6H) Step 7 [3-(1-Adamantyl)-4-曱oxy-5-morpholinylphenyl]-2-(5',6,-di^ethoxy-3'-imino-spiro[cyclopropan-1,1'-isoalpha] Lin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxy sulphide [cyclopropanone-1,3'-isobendron)-1,-imine hydrobromide The acid salt 7d (246 mg, 1 mmol) was dissolved in 6 mL of tetrahydrofuran, and 1-[3-(1-Goldenyl)-4-methoxy-5-morphinephenyl]-2-di-(e-ketone) 17h was added. (516 mg, 1.15 mmol) and triethylamine (0.55 mL, 1.08 mmol). After filtration, the filter cake was washed with n-hexane (5 mL×2) and water (10 mL×2) and dried in vacuo to give the title product [3-(1-adamantyl)-4~methoxy-5-morpholinyl]- 2-(5',6'-diethoxy-3,-imino-131 95255 201242964 snail [cyclopropyl--1,1'-iso-°------) Hydrogen acid I? (317 mg white powder), yield: 22.9%. MS m/z (ESI): 614 [M+l] H NMR (400 MHz, DMS0-i/6, ppm): δ 9.64 {br. s, 1H) 9.08 (br. s, 1H), 7.87 (s , 1H), 7.59 (d, /= 1.6 Hz, 1H), 7.52 (d, /= 1.6 Hz, 1H), 7.05 (s, 1H), 5.20 (s, 2H), 4.17 (q, / = 7. 2 Hz, 2H), 4.11 (q, / = 7. 2 Hz, 2H), 3.96 (s, 3H), 3.82 (m, 4H), 3.01 (m, 4H), 2.07 (m, 9H), 1.76 ( m, 6H), 1.75-1.60 (m, 4H), 1.40 (m, 6H) Example 18 2*~[8-S-butyl-6-[2-(5',6'-diethoxy_ 3 -Imino-spiral [cyclopropane~1,1'-iso-bamboo-dip]-2'-yl)ethidyl]_2,3--gas-1,4-benzo-11 _4-based] ethyl acetate hydrogen acetate &gt;

First step 2, [8-tert-butyl-6-[2-(5',6'-diethoxy-3'-imino-spiro[cyclopropan-1,1'-iso- 0 0]-2'-yl)acetate]-2,3-diindole-1,4-benzo-oxazin-4-yl]ethyl acetate hydrobromide 132 95255 201242964 5',6' - Diethoxyspiro[cyclopropane-1,3'-isoporphyrin]-oxime-imine oxime bromide 7d (252mg, 1. 02mmol) was dissolved in 5mL of tetrahydrofuran, and 2-[6 was added. -(2-bromo-ethenyl)-8-tert-butyl-2,3-dihydro-1,4-benzox-oxo-methyl-4-yl]-acetic acid ethyl acetate 5e (440 mg, l.10 mmol And triethylamine (0.15 mL, 1.08 mmol), and the reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL×2) and water (10mL×2) and dried in vacuo to give the title product 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-3) '-Imino-spiro[cyclopropane-1, fluorene-isoindole]-2'-yl)ethinyl]-2,3-dihydro-1,4-stupyl and oxazin-4-yl Ethyl acetate hydrobromide 22 (317 mg, yellow powder), yield: 50.8%. MS m/z (ESI): 565 [M+l] NMR (400 MHz, DMSO-fife, ppm): δ 9.67 (br. s, m) 9.16 (br. s, 1H), 7.92 (s, 1H), 7.30 (d, /= 1.2 Hz, 1H), 7.08 (d, 1.2 Hz' 1H), 7.05 (s, 1H), 5.12 (s, 2H), 4.31 (m, 4H), 4.12 (m, 4H), 3.51 (m, 2H), L68 φ -1. 60 (m, 4H), 1. 38 (m, 15H), 1. 20 (t, /= 7. 2 Hz, 3H) Example 19 1 -(8-tert-butyl 4-mercapto-2,3-dihydro-1,4-benzo-indole-6-yl)- 2__ (5',6'-diethoxy-3' - Imino-spiro[cyclopropane-1, Γ-isoindole]-2'-yl)ethanone hydrobromide 95255 133 201242964

The first step is 1-(8-tert-butyl-4-methyl-2,3-diaza-1,4-benzo-β-carbo- 6-yl)-acetamidine 1-(8-tert-butyl-3) , 4-dihydro-2Η-1,4-benzoxazin-6-yl) Ethyl ketone 5c (1.5 g, 6.4 mmol) was dissolved in 20 mL of acetone and potassium carbonate (1.78 g, 12.8 mmol) was added. The mixture was stirred for 40 hours with magnetic methane (4.66 g, 32. lmmol). The organic layer was combined with EtOAc (EtOAc (EtOAc) (EtOAc) -(8-tert-butyl-4-methyl-2,3-dihydro-1,4-benzoxazin-6-yl)ethanone 19a (375 mg, brown oil), yield: 23 6 %. 4 R (400 MHz, CDC13, ppm): δ 7.40 (d, /= 2.0 Hz, 1H), 7.26 (d, /= 2.0 Hz, 1H), 4.37-4.40 (m, 2H), 3.34-3.36 ( m, 2H), 2.99 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H) Step 2 2-Mer-1-(8-tert-butyl-4_fluorenyl-2, 3- Dihydro-1,4-benzoxazine-6-yl)ethanone 1-(8-tert-butyl-4-indenyl-2,3-dihydro-1,4-benzoxazine-6 - 134 95255 201242964 base) Ethyl ketone 19a (511 mg, 2. lmmol) was dissolved in 6 mL of acetic acid, tribromopyridinium rust salt (800 mg, 2.48 mmol) was added, and the reaction was stirred for 3 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) And oxazol-6-yl)ethanone 19b (200 mg, yellow oil), yield: 29.6%. Ή NMR (400 MHz, CDCh, ppm): δ 7.42 (d, / = 2. 0 Hz, 1H), 7.27 (d, /= 2.0 Hz, 1H), 4. 45 (s, 2H), 4.39- 4.42 (m, 2H), 3. 35-3. 38 (m, 2H), 2. 99 (s, 3H), 1.44(s, 9H) Step 3 1-(8-tert-Butyl 4-methyl) -2,3-dihydro-1,4-benzoxazin-6-yl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane_oxime, 1, _ 吲哚 吲哚 ] ] ] ] ] ] ] ] ] 将 将 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 ,-imine hydrobromide 7d (249mg, l. 〇lmmol) and 2_bromo-indole-(7)-tert-butyl-4-mercapto-2,3-dihydro-1,4-benzoxazine Ethyl ketone i9b (39 〇 mg, 1. 2 mmol) was dissolved in 6 mL of tetrahydrofuran, and triethylamine (〇·15 mL, 1.08 mmol) was added. The reaction was stirred for 24 hours. Filtration, filter cake washed with n-hexane (i 〇 mL) and water (10 raLx3), dried in vacuo to give the title product 丨_(8-tert-butyl 4-methyl-2, 3-dihydro-1,4-benzene And oxazine _6_yl)_2_(5,6, _diethoxy-3'-imino-spiro[cyclopropane&lt;, hydrazine, _isoporphyrin]_2,-yl) ethyl ketone Hydrobromide 19 (316 mg, pale yellow powder), yield: 54. 135 95255 201242964 MS m/z (ESI): 492 [M+l] * NMR (400 MHz, DMSO-i/e, ppm): δ 9.69 (br. s, 1H), 9.14 (br. s, 1H ), 7.94 (s, 1H), 7.30 (d, /= 1.6 Hz, 1H), 7. 22 (d, /= 1.6 Hz, 1H), 7. 05 (s, 1H), 5. 18 (s, 2H), 4.35 (ra, 2H), 4.13 (m, 4H), 3.07 (m, 2H), 2.94 (s, 3H), 1.70 - 1.60 (m, 4H), 1.38 (m, i5H) Example 20 1 -[3-(4-Ethyl sulfanyl-1-yl)-5-tert-butyl-4-methoxyphenyl]- 2_(5',6'-diethoxy-3'-Asia Amino-spiro[cyclopropane-1,1,-iso-πbendolin]_2'-yl)ethanone hydrogenate

First step 1-[4-[3-tert-butyl-5-(1,1-dimethoxyethyl)-2-nonyloxyphenyl] α 底 _ _ _ ke ke ke ke 1-tert-Butyl-5-(1,1-dimethoxyethyl)-3-iodo-2-indolylbenzene 2f (11.5 g, 30.42 mmol) was dissolved in 60 mL of dioxane. Add 136 95255 201242964 to 1_σ-endazine~1-yl-ethanone (5.7 g, 39.55 mmol) 'Tris(dibenzylidenepropene) II (1.15 g, 10%), 4, 5-double (Diphenylphosphine)-9,9-dimethyloxa onion (88 〇, i.52 mm 〇i) and sodium tert-butoxide (5.85 g, 60.84 mmol), 60 C to disturb the reaction for 7 hours. The reaction mixture was poured into 3 mL of ice water and 150 mL of EtOAc. EtOAc (EtOAc m. The title product 1-[4-[3-tert-butyl-5-(1,1-dimethoxyethyl)-2-decyloxy]pyrazin-1-yl]ethanone 20a was obtained directly. One step reaction. The second step of 1_[3_(4~ethinylpiperazin-1-yl)-5-tert-butyl-4-decyloxyphenyl]ethanone will be [443-tert-butyl-5-(1, 1-Dimethoxyethyl)-2-methoxyphenyl] oxazin-1-yl]ethanone 2〇a (6.7 g, 17.7 mmol) was dissolved in 50 mL of di-methane and added Acetic acid (3.2 g, 53 nmol), the reaction was stirred for 12 hours, concentrated under reduced pressure, and the residue obtained was purified by hexanes column chromatography eluting with the eluent system to give the title product [3-(4-ethylhydrazine). 0%. The yield of 2,0%. MS m/z (ESI): 333 [M+l].H NMR (400 MHz, CDCh, ppm): δ 7.68 (d, / = 2. 〇Hz, 1H), 7.48 (d, /= 2.0 Hz, 1H), 3.99 (s, 3H), 3.81 (m, 2H), 3. 66 (m, 2H), 3.07 (m, 4H), 2.56 (s, 3H), 2.15 (s, 3H), 1.41 (s , 9H) The third step 137 95255 201242964 卜 [3-(4-Ethylpiperazin-1-yl)-5-tert-butyl-4-methoxyphenyl]-2 bromo-ethanone 1- [3-(4-Ethylbenzylidene-1-yl)-5-tert-butyl-4-methoxyphenyl]ethanone 20b (1.8 g, 5. lmmol) was dissolved in 15 mL of methane. Among them, acetic acid (1.2 g, 20.4 mmol) and tribromopyridinium salt (2. lg, 5 - 36 mmol) were added, and the reaction was stirred for 12 hours. The residue was purified by EtOAc (EtOAc) elut elut - 曱 笨 笨 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Ή NMR (400 MHz, CDCh, ppm): δ 7.72 (d, / = 2. 0 Hz, 1H), 7.51 (d, /= 2.0 Hz, 1H), 4.40 (s, 2H), 4.01 (s&gt; 3H), 3.81 (in, 2H), 3.66 (m, 2H), 3.07 (m, 4H), 2.16 (s, 3H), 1.41 (s, 9H) Step 4 l-[3-(4-Ethyl) Piperazine-l-yl)-5-tert-butyl-4-methoxyphenyl]-2-(5',6'-diethoxy-3'-imido-spiro[cyclopropane- 1,Γ-isoporphyrin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxyspiro[cyclopropane-1,3'-isoindoline]-1, — The imine hydrobromide 7d (125mg, 0.5mmol) was dissolved in 3mL of tetrahydrofuran and added 1-[3-(4-ethenyl-l-yl-1)-5-tert-butyl-4-methyl Oxyphenyl]-2 bromo-ethanone 20c (206 mg, 0.5 mmol) and triethylamine (76 mg, 0.75 mmol) were stirred for 48 hours. Filtration of the filter cake with tetrahydrofuran (1 mL) &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& -tert-butyl-4-methyl 138 95255 201242964 oxy-benzyl]-2-(5,6-diethoxy_3'-imino]-spiro[cyclopropene-1, Γ-iso σ-induced Duolin]-2'-yl)ethanone hydrogen oxalate 20 (62 mg, white solid), yield: 21.5%. MS ra/z (ESI): 577 [M+l] lH NMR (400 MHz, DMS0-i/6, ppm): δ 9.64 (Z?r. s,1H) 9.08 (br. s, 1H), 7.86 (s, 1H), 7.65 (d, / = 2. 0 Hz, 1H), 7.55 (d, /= 2.0 Hz, 1H), 7.05 (s, 1H), 5.18 (Sj 2H), 4.41 (m, 4H) ), 3.98 (s, 3H), 3.67 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.06 (s, 3H), 1.73 -1.60 (m, 4H), 1.42-1.36 (m, 15H) Example 21 1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5',6'-diethoxy-3'-imino-- Spiro [cyclopropane-hydrazine, hydrazine, -isoporphyrin]_2'-yl) ethyl ketone hydroperate

The first step 1~(3,5-di-tert-butyl-4-yl-phenyl)acetamidine with dry ice ~ propylene - bath, aluminum chloride (1. 31g, 9.79mmol) was dissolved in 20mL of dichloromethane Add 2 6_di-tert-butylphenol ld (2 〇g, 139 95255 201242964 9. 63mmol), stir the reaction for 1 hour, add B-chlorine le (0. 401mL, 9. 79mmol), continue to disturb Reaction for 4 hours. 2 hr of this ice water was added to the reaction solution, and the mixture was extracted with dioxane (40 mL×3), and the organic phase was combined, washed with saturated sodium carbonate solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title product was 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone 21a (1.98 g, m. MS m/z (ESI): 249 [M+l] Step 2 1-(3, 5-di-tert-butyl-4-methoxyphenyl)ethanone φ 1-(3, 5-di-uncle Butyl-4-hydroxyphenyl)ethanone 21a (i. 29 g, 5. 2 mmol) was dissolved in 50 mL of acetone, and then charged with carbonic acid (i.43 g, 10.34 mmol) and toluene-4-sulfonic acid The ester (1.93 g, 10.36 ramol), 5 〇〇c was stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford the title product (3,5-di-tert-butyl-4-methoxyphenyl)ethanone 2ib (1.03) g,红红色油), yield: 75.4%. MS m/z (ESI): 263 [M+l] · Step 3 2-bromo-1-(3,5-di-tert-butyl-4-ylphenyl)ethanone 401 3,5-di-tert-butyl _41 oxyphenyl) ethyl ketone (711 mg, 2.71 curry 1) was dissolved in 2 mL of gas, copper bromide (964 mg, 5.42 mmol) was added, and the reaction was stirred for 12 hours. . Filtration, the filtrate was depressurized and condensed. The residue obtained by the eluent system was chromatographed to obtain the title product 2-bromo-1-(3,b-di-tert-butyl-4-phenylbenzene. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. MS m/z (ESI): 343 [M+l] Step 4 1-(3,5-di-tert-butyl-4-decyloxyphenyl)-2-(5,6,2-diethoxy Benzyl-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2,-yl)ethylidene hydrobromide salt 5',6'-diethoxy snail Propane-1,3'-isoindoline]-1,_imine hydrogenate salt 7d (198mg, 0.8mmol) dissolved in 3mL tetrahydrofuran• in the addition of 2-bromo-1-(3, 5-Di-tert-butyl-4-methoxyphenyl)ethanone 21c (303 mg, 0.89 mmol) and triethylamine (15 mL, EtOAc) Filtration, the filter cake was washed with tetrahydrofuran (imL), water (2 mL mL) and n-hexane (1 〇hiLx2) and dried in vacuo to give the title product ι_(3,5-di-tert-butyl-4-decyloxyphenyl) )-2-(5',6'-diethoxy-3,-imino-spiro[cyclopropan-1,1'-isoindole]-2'-yl)ethanone hydrobromide 1%。 Salt 21 (128 mg, white powder), yield: 27.1%. • MS m/z (ESI): 507 [M+l] ^ NMR (400 MHz, DMSO-i/e, ppm): δ 9.70 (br. s, 1H), 9. 15 (br. s, 1H) , 7. 93 (s, 1H), 7. 91 (s, 2H), 7. 06 (s, 1H), 5.23 (s, 2H), 4. 18(q, / = 7. 2 Hz, 2H) , 4. 12 (q, /= 7· 2 Hz, 2H), 3. 71 (s, 3H), 1· 76- 1. 60 (m, 2H), 1. 45 (s, 18H), 1.39 ( m, 6H) Example 22 1 -(3,5-di-tert-butylphenyl)-2-(5',6'-diethoxy-3'-imino-spiro[cyclopropane-1, Γ-Isoporphyrin]-2'-yl)ethanone hydrobromide 141 95255 201242964

22a 22b 22c 22 The first step of 1-(3,5-di-tert-butyl-phenyl)acetamidine dry ice-Bin 嗣 bath under 'will be 1-di-3,5-di-tert-butyl-benzene 22a (3. 58 g, 13. 31 mmol) dissolved in 26 mL of tetrakis sigma, added tetramethylethylenediamine (2.2 mL, 14.6 mmol) and n-butyl hydride (5. 85 mL ' 14. 6 mmol), scrambled After reacting for 1 hour, dimercaptoacetamide (2.66 mL, 26.6 mmol) was added, and the reaction was further stirred for 2 hours. Add 20 mL of saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (20 mL×3), combine the organic phase, wash the mixture with water (10 mL×2) and saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, filtrate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) ()), yield: 58.2%. *Η NMR (400 MHz, CDCla, ppm): δ 7.82 (s, 2H), 7.66 (s, 1H), 2.62 (s, 3H), 1.37 (s, 18H) 3,5-di-tert-butyl-phenyl)acetamidine was dissolved in 100 mL of chloroform with 1-(3,5-di-tert-butyl-phenyl)ethyl@- 221) (3.8 笞, 16.41111111〇1). The solution was stirred for 24 hours at 37 ° C by adding copper ( 7.32 g, 32.7 mmol), 142 95255 201242964. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by eluent column chromatography eluting with eluent system B to give the title product 2 _ - - - - - - - - - - - - - - - - - - - - - (3.4 g, pale yellow solid), Yield: 66.8%. !H NMR (400 MHz, CDCh, ppm): δ 7.85 (s, 2H), 7. 7〇(Sj 1H), 4.48 (s, 2H), 1.37 (s, 18H) Step 3 1-(3, 5-di-tert-butylphenyl)-2-(5,6'-diethoxy-3,-imino-spiro[%-propyl _1,1-iso- 丨 丨 朵 朵 ]] -2'yl) acetamidine salt 5',6'-diethoxyspiro[cyclopropane-1,3'-isoindoline]-1,imine hydrobromide 7d (131mg , 0. 53 mmol) dissolved in 5 mL of tetrahydrofuran 'Addition of 2-bromo-1-(3,5-di-tert-butyl-phenyl)-ethanone 22c (193 mg, 0.62 mmol) and triethylamine (〇. , 〇. 72mmol), stir the reaction for 12 hours. Filtration, the filter cake was washed with THF (1 mL×2) and water (1 〇mL×3) and dried in vacuo to give the title product 1-(3,5-di-tert-butylphenyl)-2-(5,,6, -? Ethoxy-3'-imino-spiro[cyclopropane-1,1,-isoindoline]-2,-yl) ethyl ketone hydrobromide 22 (67 mg, white powder), yield: 27 . 1%. MS m/z (ESI): 477 [M+l] H NMR (400 MHz, dUSO-ώ, ppm): δ 9.66 (br. s, 1H), 9. 16 (Z?r. s, 1H), 7.89 (s, 1H), 7. 84 (s, 2H), 7. 78 (s, 1H), 7.06 (s, 1H), 5.24 (s, 2H), 4. 18 (q, / = 7. 2 Hz, 2H), 4. 11 (q, J= 7. 2 Hz, 2H), 1. 76 -1. 61 (m, 4H), 1. 40 (m, 6H), 1.36 (s, 18H) Example 23 143 95255 201242964 1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-(5',6'-diethoxy-7'-fluoro-3'-imino- Spiro [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl) ethyl ketone hydrobromide

The first step is to dissolve 2-fluorophenol 23a (210 g, 1.88 mol) in 500 mL of gas, and add liquid bromine (94 mL, 1.88 mol) at room temperature. The reaction was disturbed for 2 hours. Add 100 mL of saturated sodium sulfite solution, extract with dichloromethane (100 mL×3), combine the organic phase, wash the strip with 10 mL of saturated sodium carbonate solution, dry over anhydrous sulphuric acid, sluice, and concentrate under reduced pressure to give the title product 4-bromo- 2-fluorophenol 23b (321 g, pale yellow oil), yield: 90.2%. MS m/z (ESI): 191 [M+l] 丽 R (400 MHz, CDC13, ppm): δ 7.21 (d, /= 2.4 Hz, 1H), 7.71 (m, 1H), 6.98 (m, 1H) ), 6.19 (br. s, 1H) The second step 5 - desert - 3 - gas - 2 - trans- phenyl - waking 144 95255 201242964 4-bromo-2-fluorobenzene 23b (170g, 0.89mol) Dissolved in 600 mL of difluoroacetic acid 'Addition of urotropine (225 g, 1. 6 mol 1)' reflux reaction for 5 hours. After cooling to room temperature, the reaction solution was poured into 1 L of water, and added to 300 mL of 50% sulfuric acid solution 'filtered'. The filter cake was washed with 20 mL of ethanol and dried in vacuo to give the title product 5-bromo-3-fluoro-2-hydroxy-benzaldehyde. 2%。 23c (90 g, yellow solid), yield: 46.2%. MS m/z (ESI): 219 [M+l] NMR (400 MHz, CDCh, ppm): 5 10.87 (Z?r. s, 1H), 9.88 • (s, 1H), 7.50 (m, 1H) ), 7.28 (s, 1H) The third step 5 - desert-3-fluoro-1,2-diphenyl will be 5 - desert-3-fluoro-2-pyridyl-benzoquinone 23c (80 g, 〇. 37 mol) was dissolved in 402 mL of 1 M sodium hydroxide solution, 402 mL of hydrogen peroxide was added, and the reaction was stirred for 3 hours. To the reaction mixture, a solution of 100 mL of saturated sodium sulfite was added, and the mixture was extracted with ethyl acetate (200 mL×4), and the organic phase was combined and dried with EtOAc EtOAc EtOAc. 4%。 The product 5-bromo-3-fluoro-1,2-diphenyl, 23d (60 g, colorless solid), yield: 79.4%. MS m/z (ESI): 205 [Ml] Step 4 5-bromo-1,2-diethoxy-3-fluoro-benzene 5-bromo-3-fail-1,2-diphenyl 23d (20.7 g, 〇. im〇l) was dissolved in 150 mL of sulfoxide, and ethyl iodide (24.2 mL, 〇·3 mol) and potassium carbonate (34 _5 g, 0.25 mol) were added, and the mixture was stirred at 50 ° C for 3.5 hours. To a solution of 145 95255 201242964, 600 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL mL), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title compound, md, m. NMR (400 MHz, CDCh, ppm): δ 6.89 (d, /= 2.0 Hz 1H), 6.82 (t, J = 2.0 Hz, 1H), 4.09 (m, 4H), I.45 (t&gt; J = 1.2 Hz, 3H), 1.36 (t, / = 7. 2 Hz, 3H) Step 5 1,2-Di--4, 5-Diethoxy-3-Den-Benzene 5-Bromo-1,2 -diethoxy-3-fluoro-benzene 23e (15 g, O. 〇 57 mol) dissolved in 100 mL of acetic acid, sodium acetate (6.22 g, 0·076 mol) and liquid bromine (12.12 g, 0.076 mol) The reaction was stirred at 50 ° C for 5 hours. After adding 100 mL of water, it was extracted with n-hexane (100 mL×3), and the organic phase was combined, washed with saturated sodium sulfate solution (50 mL), dried over anhydrous magnesium sulfate, and filtered, and filtrated to give the title product 1,2-dibromo-4. 0%。 5-diethoxy-3-fluoro-benzene 23f (11 舀, colorless oil), yield: 56.0%. 4 R (400 MHz, CDC13, ppm): δ 7. 〇5 (s, 1H), 4. 29 (Q, /= 6.4 Hz, 2H), 4. 19 (q, /= 8.0 Hz, 2H) , l.52 /= 6.4 Hz, 3H), 1.41 (t, / = 8. 〇Hz, 3H) Step 6 4, 5-Diethoxy-3-fluoro-dicarbonitrile 1,2-dibromo -4,5-Diethoxy-3-fluoro-benzene 23f (n. U, 〇. 032 mol) was dissolved in 60 mL of N,N-dimercaptocarboxamide, followed by the addition of cyanide 95255 146 201242964 cuprous ( 11.6 g, 0.13 mol) and cuprous halide (6.17 g, 0.032 mol) were reacted under reflux for 8 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc). The residue was purified by EtOAc EtOAc (EtOAc) elute 34. 7%. JH NMR (400 MHz, CDCh, ppm): δ 6.83 (s, 1H), 4.55 (m, # 2H), 4.13 (m, 2H), 1.48 (t, /=6. 0 Hz, 3H), 1.39 ( t, / = 6.8 Hz, 3H) The seventh step 5',6'-diethoxy-7'-fluoro-spiro[cyclopropyl-i,3, _iso- 0-induce]_1'- Amine 5',6'-diethoxy-4'-fluoro-spiro[cyclopropanone__ι,3, _isoindole]_ι,_ an amine in an ice bath, 4,5-diethoxy Base-3-fluorine, dinitrile 232 (2.26§, 9. 66匪〇1) dissolved in l〇〇mL 谜 ' ' Add tetraisopropyl titanate (3. 胤, 10.75 mmol) and ethyl bromide Town (7 imL, 213 Radisson 1), the reaction was allowed to react for 2 hours. When 55 mL of methanol was added to the reaction mixture, the obtained residue was purified by column chromatography using eluent system A to give the title product 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane, [ ,3,-iso(tetra)lead,imine 23h and 5,6'-diethoxy_4,,fluorine,cyclopropanone-U,-iso-portal «Η,_imine 23K955 slightly dark red powder ), yield: 37 4%. MS m/z (ESI): 265 [M+l] 95255 147 201242964 4 NMR (400 MHz, DMS0-忒, ppm): δ 7. 01 (s, 1H), 4. 14 (m, 4H), 1.82 (m, 2H), 1.67 (m, 2H), 1.34 (m, 6H) 4 NMR (400 MHz, DMSO-i/6, ppm): δ 7. 94 (s, ih), 4.17 (m, 4H) , 1.81 (m, 2H), 1.69 (m, 2H), 1.34 (m, 6H) Step 8 1-(3, 5-di-tert-butyl-4-phenylphenyl)-2-(5', 6'-Diethoxy_7,-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2, __yl)ethanone hydrobromide 5 ,6-diethoxy-7'-fluoro-spiro[cyclopropan-l,3'-isoπ-introduced π-porphyrin]-indole-imine 23h and 5',6'-diethoxy-4 ,-Fluoro-spiro[cyclopropane-1,3'-isoporphyrin; H'-imine 23i (277 mg, 1.05 nmol) was dissolved in 3 mL of tetrahydrofuran, and 2-bromo-1-(3, 5-di) was added. tert-Butyl-4-hydroxyphenyl) Ethyl ketone (352 mg, 1. 8 mmol) and triethylamine (2 mL, 1.44 mmol). Filtration, the filter cake was washed with n-hexane (1 mL mL) and water (10 mL×2) and dried in vacuo to give the title product ι (3, 5-di-tert-butylhydroxyphenyl)-2-(5',6' - Ethoxy-7'-fluoro-3,-imino-spiro[cyclopropane-1,indole-isoindoline]-2'-yl)ethanone hydrobromide 23 (I7mg, brown powder), Yield: 2.7%. MS m/z (ESI): 511 [M+l] H NMR (400 MHz, DMSO-i/6, ppm): δ 7. 95 (s, 1H), 7 79 (s, 2H), 5. 19 (s, 2H), 4.22 (q, / = 7. 2 Hz, 4H), 1.78 (m, 4H), 1.46 (s, 18H), 1.31 (t, /= 7.2 Hz, 6H) Example 24 1- (3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,β-diethoxy_4_fluoro 95255 148 201242964 -3-imino-l'l-didecyl L朵淋_2_基)乙_氮漠酸盐

The first step is 2-(3,4-diethoxy-5-fluoro-phenyl)propan-2-ol at -78 C, 5-bromo-1,2-diethoxy-3-fluoro- Benzene 23e (26.3 g, 0-lmol) was dissolved in lOOniL diethyl ether, n-butyl clock (44 mL, 0·llmol) was added, the reaction was stirred for 30 minutes, and acetone (8. lmL, 〇.llm〇1) was added. Reaction for 2 hours. 2 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL×2), and the organic phase was combined and washed with a saturated sodium carbonate solution (100 mL) and concentrated under reduced pressure to give the title product 2-(3, 4- Ethoxy-5-gas-propenyl)propan-2-drink 24a (23·7 g, yellow oil), yield: 97.9%.沱匪R (400 MHz, CDC13, ppm): δ 6. 87 (m, 1H), 6.81 (m, 1H), 4. 14 (m, 4H), 1. 57 (s, 6H), 1 . 47 (t, / = 7. 2 Hz, 3H), 1.31 (t, / = 7.2 Hz, 3H) Step 2 5-(1-azido-1-methyl-ethyl)-l,2- Diethoxy-3-fluoro-stupid 149 95255 201242964 2-(3,4-diethoxy-5-fluoro-phenyl)propan-2-ol 24a (21·97 g,0) under ice bath · 091 mol) was dissolved in 2 mL of gas, sodium azide (17.7 g, 0.27 mol) and trifluoroacetic acid (33.7 mL, 0.46 mol) were added, and the reaction was stirred for 12 hours. The organic layer was concentrated with EtOAc (EtOAc m. 5-(1-azido-1-methyl-ethyl)-1,2-diethoxy-3-fluoro-benzene 24b (24. 1 g, yellow oil), yield: 99. 2 %. NMR NMR (400 MHz, CDCh, ppm): δ 6. 75 (m, 2H), 4. 12 (m, 4H), 1.60 (s, 6H), 1.45 (t, / = 7. 2 Hz, 3H) , 1.36 (t, / = 7. 2 Hz, 3H) The third step 1-(1-azido-1-methyl-ethyl)-2-independent _4, 5-diethoxy-3- gas -Benzene 5-(1-azido-1-indenyl-ethyl)-1,2-diethoxy-3-fluoro-benzene 24b (21.4 g, 0.08 mol) was dissolved in 200 mL of acetic acid, and acetic acid was added. Sodium (13. lg, 0.16 mol) and liquid bromine (8 mL, 0.16 mol) were stirred for 48 hours. Add 30 mL of saturated sodium sulfite solution, extract with n-hexane (150 mL×3), combine the organic phases, wash with saturated sodium bicarbonate solution (150 mL×2) and saturated sodium carbonate solution (150 mL), dry with anhydrous sulfuric acid, filter, filtrate decompression Concentration gave the title product 1-(1-azido-1 -methyl-ethyl)-2-bromo-4, 5-diethoxy-3-fluoro-br. 24c (20.4 g, yellow oil) , yield: 73. 5%. *11 NMR (400 MHz, CDCh, ppm): δ 7.01 (d, / = 2. 0 Hz, 1H), 4. 16 (m, 4H), 1. 83 (s, 6H), 1. 49 (t , / = 7. 2 Hz, 150 95255 201242964 3H),1·41 (t, / = 7.2 Hz, 3H) The fourth step 5, 6-monoethoxy-7-n,3_dimethyl-iso, 嗓1-amine 1-(1-azido-1-indenyl-ethyl)-2-bromo-4, 5-diethoxy-3-fluoro-benzene 24c (10 g, 28.8 mmol) was dissolved in 1 〇 〇mL dimethyl sulfoxide, adding copper cyanide (5"6g, 57.6mmol) and cuprous bismuth (1〇竑^ ugly (4)' tear (10) mixed reaction 丨 hours ^ said water and fine this ethyl acetate, The organic phase is washed with 300 mL of hydrochloric acid, and the aqueous phase is combined. The sodium hydroxide solution of this type is used to adjust Qiu to ^. Water extract of acetic acid ethyl acetate (10) mL×3), and the organic phase is combined with dilute ammonia water (2) and Saturated gasified sodium solution silk (2GGmL) 'anhydrous sulfur-drying, minus, the filtrate was concentrated under reduced pressure to give the title product 5,6-diethoxy, 7-gas_3,3_dimethyl-isoindole- 1-amine 24d (0.9 g, gray solid), yield: 115%. MS m/z (ESI): 266 [M+l] H NMR (400 MHz, CDCh, ppm): δ 7. 〇1 (s, 1H), 4 18 (m, s. 2H), 4. 10 (m) , 2H), 1. 48 (t, / 2 Hz, 3H), i 44 (s, 6H), 1.37 (t, / = 7.2 Hz, 3H) Step 5 1-(3,5-di-tert-butyl -4-Phenylphenyl)~2, (5,6-diethoxy_4_|1 Iimino _ 1 ' 1 _1 methyl-iso-dolin, 2-yl) acetamidine 5,6-diethoxy-7-fluoro-3, dimethyl-isodecyl+amine 24d (266mg, 1 〇1) was dissolved in 7mL of N,N-dimercaptoamine, added 2_ Mo-Bu (10)-di-tert-butyl + phenyl group ~ the same (1) period, 1. lmmol) 'Search and mix reaction for 12 hours. To the reaction mixture, 7 mL of water was added, 95255 151 201242964 was extracted with ethyl acetate (25 mL×3), washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent column chromatography to afford the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6-diethoxy- 4-Fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrogen oxalate 24 (110%, yellow solid), yield: 21.6%. MS ra/z (ESI): 513 [M+l]^ NMR (400 MHz, DMSO-^e, ppm): δ 9.37 (br. s, 1H), 8. 98 (Z?r. s, 1H) , 8. 05 (Z?r. s, 1H), 7. 83 (s, 2H), 7.48 (s, 1H), 5.47(s, 2H), 4. 26 (in, 2H), 4. ll( m, 2H), 1.51 (s, 6H), 1.44 (s, 18H), 1.41 (t, /=7.2 Hz, 3H), 1.31 (t, / = 7. 2 Hz, 3H) Example 2 5 1-(3-tert-butyl-4-yloxy-5-pyrrolidin-1-yl-phenyl)-2-(7-imino-2,5-dimethyl-phenyl-pyrrolidine [3, 4-doing &gt; than 0 to 6-yl) ethyl ketone hydrobromide

First step 152 95255 201242964 1-(3-tert-butyl-4-methoxy-5-pyrrole-1-yl-phenyl)-2-(7-imino-2,5-dimethyl -5-phenyl-pyrrolo[3,4-Z?]pyridin-6-yl)ethanone hydrobromide salt 2, 5-dimercapto-5-phenyl-6 and -pyrrolo[3, 4-anthracene pyridine-7-imine 9f (237ing, 1 mmol) and 2-di-1-(3-tert-butyl-4-decyloxy-5_0pyroxy-1-yl-phenyl)ethanone 8d (424. 8 mg, 1. 2 mmol) was dissolved in 3 mL of N,N-didecylamine, and the reaction was stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium carbonate solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography to purify the residue obtained by eluent system A to give the title product 1-(3-tert-butyl-4-decyloxy-5-«* bilox-1-yl-phenyl)-2-( 7-Imino-2,5-dimercapto-5-phenyl-indolo[3,4-/?]pyridin-6-yl)ethanone hydrobromide 25 (13〇11^, yellow solid ), Yield: 22.0%. MS m/z (ESI): 512 [M+l] φ R (400 MHz, DMSO-d, ppm): δ 7. 93 (d, /= 7. 6 Hz, 1H), 7.65 (d, / =7. 6 Hz, 1H), 7.37 (m, 7H), 5.04 (d, /= 16.8 Hz, 1H), 3.82 (s, 3H), 3. 14 (m, 4H), 2.74 (s, 3H) , 1.99 (s, 3H), 1.90 (m, 4H), 1.36 (s, 9H) Example 26 1-(3-tert-butyl-4-decyloxy-5-σ ratio n each -1-yl group -phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 153 95255 201242964

1-(3-tert-butyl-4-methoxy-5-.pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imine 1,1-dimercapto-isoindolin-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3-dimercapto-isoindole哚-: 1-amine 24 {1 (266 mg, 1 mmol) was dissolved in 7 mL of N,N-didecylamine, and 2-bromo-1-(3-tert-butyl-4-decyloxy-5 was added. Pyrrolidin-1-yl-phenyl)ethanone 8d (390 mg, 1.1 mmol) was stirred for 12 hours. To the reaction mixture was added EtOAc (EtOAc) (EtOAc) The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc) -2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindole-2-yl)ethanone argon bromide 26 (6 l mg, Yellow solid), Yield: 11.3%. MS m/z (ESI): 540 [M+l] WNMRMOO MHz, DMSO-form, ppm): δ 7.50 (d, /= 2.0 Hz, 1H), 7. 45 (s, 2H), 5.41 (s, 2H), 4. 27(q, /=7. 2 Hz, 2H), 4.13 154 95255 201242964 (q, /=7. 2 Hz, 2H), 3. 67(s, 3H), 3. 19(m , 4H), 1. 94(m, 4H), 1.51(s, 6H), 1.41(m, 12H), 1.32(t, /=7.2 Hz, 3H) Example 27 l-(3-tert-butyl) 4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-didecyl-isoporphyrin -2-yl)ethanone hydrobromide

The first step is 1-(3-tert-butyl-4-methoxy-5-morpholinyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-dimercapto-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3-dimercapto-isoindole-p-amine 24d (400 mg, 1.5 mmol) was dissolved in 10 mL of N,N-didecylguanamine and added to 2_'; odor-1 -(3-tert-butyl-4-decyloxy-5-morphinylphenyl) 2h (610 mg, 1.65 mmol), the reaction was stirred for 12 hours. After adding 100 mL of water to the reaction mixture, the mixture was extracted with ethyl acetate (50 mL×5), and the organic phase was combined, washed with water (50×3 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate The title product 1-(3-tert-butyl-4-decyloxy-5-nor-phenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1 - dimethyl-isoindoline-2-yl)ethanone hydrobromide 27 (84 mg, yellow solid), yield: 8.4. 155 95255 201242964 MS m/z (ESI): 556 [M+l] *H NMR (400 MHz, DMSO-i/e, 8. 99 (br. s, 1H), 7. 67 (d, PPm): δ 9.35 {br. s, 1H), =2. 0 Hz, 1H), 7. 59 (d, /=2.0Hz, U〇, 7.46(S' 1H), 5 47 (s, 2H), 4 27 (q, /=7.2HZ, 2H), 4.13 (q, /=72Hz, 2H), 4 〇i (s, 3H), 3.84 (m, 4H), 3.04 (m, 4H), 158 (s, 6H) ), l 41 (m, 12H), 1. 32 (t, = 7. 2 3h) Example 28 [3-tert-butyl-4-methoxy-5-(1, octyl)phenyl ]_2(56-diethoxy-4-fluoro-3-imino-1,1-dimethyl-iso-decyl-2-yl) acetonitrile

The first step of the barium salt 1-[3-tert-butyl-4-decyloxy-5-(1~piperidinyl)phenyl]- 2_(5,6-diethoxy-4-fluoro-3 -imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3-dimethyl- Isoindole-1-amine 24d (266 mg, 1.0 mmol) was dissolved in 7 mL of N,N-didecylamine, and 2- -1-[3-tert-butyl-4-methoxy- 5-(1-Phenyl)phenyl]ethanone 156 95255 201242964 12b (400 mg, 1. lmmol), the reaction was stirred for 12 hours. 70 mL of water was added to the reaction mixture, and the mixture was combined with EtOAc EtOAc EtOAc (EtOAc) 'Filtering to give the title product i_[3_tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3- Imidyl-1,1-dimercapto-iso, π-linolin-2-yl) ethyl ketone hydrobromide 28 (116 mg, white solid), yield: 20.9%. MS ra/z (ESI): 554 [M+l] _ 丨H NMR (400 MHz, DMSO-忒, ppm): δ 9· 27 (Z?r·s, 1H), 8.95 (br. s, 1H ), 7.64 (d, / = 2. 0 Hz, 1H), 7.59 (d, /= 2.0 Hz, 1H), 7.45 (s, 1H), 5.41 (s, 2H), 4.27 (q, /= 7. 2 Hz, 2H), 4.13 (q, / = 7. 2 Hz, 2H), 3.98 (s, 3H), 2.99 (m, 4H), 1.73 (m, 4H), 1.57 (m, 2H), 1.51 ( s, 6H), 1.39 (m, 12H), I.34 (t&gt; / = 7.2 Hz, 3H) Example 29 φ N-[3-tert-butyl-5-[2-(5, 6-di-B) Oxy_4_fluoro_3_iminobisdidecyl-isoindoline-2-yl)ethenyl]_2_decyloxyphenyl]acetamide hydrobromide

157 95255 201242964 First step N-[3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-didecyl-isoindole) Porphyrin-2-yl)ethinyl]-2-indolylphenyl]acetamide hydrobromide 5,6-diethoxy-7-fluoro1-3,3-dimethyl- Iso'1 〇 〇 -1_amine 24 (1 (266 mg, 1.0 mmol) was dissolved in 6 mL of N,N-dimethyl decylamine, and N-[5-(2-bromoethenyl)-3 was added. -tert-Butyl-2-decyloxyphenyl]acetamide 13b (380 mg, 1.1 mmol), stirred for 12 hours. Add 100 mL of water to the reaction mixture and extract with ethyl acetate (5 〇mL×3), and combine The organic phase was washed with water (50×2 mL) and brine (5··········· 5,6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-iso-indolino-2-yl)ethinyl]-2-methoxyphenyl] Acetamine hydrobromide 29 (90 mg, pale yellow solid), Yield: π. 〇%. MS m/z (ESI): 528 [M+l] 'H R (400 MHz, DMSO-, Ppm): δ 9·82 (s, 1H), 9.44 (br. s, 1H), 9.01 (br. s, 1H), 8.21 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H) ), 5.44 ( s, 2H), 4.27 (a, /= 7.2 Hz, 2H), 4. 12(q, / = 7. 2 Hz, 2H), 3.80 (s, 3H), 2. 14 (s, 3H), 1.50 (s, 6H), 1.41 (s, 9H), 1.33 (m, 6H) Example 30 1-(8-tert-butyl-4-fyl-2,3-dihydro-1,4-benzophenone嘹-6-yl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrogen Acid salt 158 95255 201242964

The first step (8-tert-butyl-4-indenyl-2,3,dihydro-i-benzoxazine-6-yl)-2-(5,6-diethoxy-4-fluoro) Aminodimethyl-isooxalin-2-yl)ethanone hydrobromide 5,6-ethoxy-7-fluoro-3,3-dimethyl-isoindole_ι- Amine 24d (300 ing, 1. 1 mmol); glutamic acid in 7 niL N, dimethyl ketoamine, 2-bromo-1-(8-tert-butyl-4-mercapto-2,3-dihydrol added -1,4-benzoxazine-6-yl) B-7b (440 mg, 1.35 mmol) 'The reaction was stirred for 12 hours. 75 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL mL). The organic phase was combined and washed with saturated sodium chloride (50 mL) and dried over anhydrous magnesium sulfate. The title product 1-(8-tert-butyl-4-mercapto-2,3-.-indole-1,4-1,4-benzo-oxo-6-yl)-2_(5,6-diethoxy __4 monox-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrogen-filled tart (80 mg, pale yellow solid), yield: 10.8%. MS m/z (ESI): 513 [M+l] 4 R (400 MHz, DMSO-c/6, ppm): δ 7.40 (s, 1H), 7 % (s, 1H), 7. 26 ( s,1H),5. 28 (s,2H),4· 36 (m,2H),4 26 (q, /= 7. 2 Hz, 2H), 4.12 (q, / = 7. 2 Hz, 2H ), 3 33 (m, 2H), 2.95 (s, 3H), 1.48 (s, 6H), 1.37 (m&gt; 12H) 95255 159 201242964 1.31 (t, J = 1.2 Hz, 3H) Example 31 2-[ 8-tert-Butyl-6-[2-(5,6-diethoxy-4~fluoro_3_imino-indenyl, j-dimethyl-isoindolin-2-yl)acetamidine Base]- 2,3~dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide

The first step 2-[8-tert-butyl-6-[2-(5,6-diethoxy~4-fluoro_3_imino)&lt;,j-dimethyl-iso-t-lin- 2-yl)ethinyl]-2,3__dihydro-1&gt;4-benzoxazin-4-yl]ethyl acetate hydrobromide 5,6-diethoxy-7-fluoro- 3,3-Dimethyl-isoindole monoamine 24d (200rag, 0.75mm〇l) was dissolved in 5mL of N,N-dimethylformamide and added 2_[6-(2-bromoethenyl) Ethyl 8-(tert-butyl-2,3-dihydroindolyl, 4-benzoxazin-4-yl)acetate 5e (330 mg, EtOAc) was stirred for 12 hr. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL mL). The organic phase was combined, washed with water (10 mL×3) and saturated sodium carbonate solution (1 〇mL×3), dried over anhydrous magnesium sulfate, filtered Concentration to give the title product 2-[8-tert-butyl-6-[2-(5,6-diethoxy_4-fluoro-3-imimido), bis-diyl-iso-decene- 2-基)乙基基]__ 2, 3_ϋ4_benzoxan 95255 160 201242964 azine-4-yl]ethyl acetate hydrobromide 31 (88 mg, pale yellow solid), yield: 17.7%. MS m/z (ESI): 584 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.44 (br. s, 1H), 8. 96 (^r. s, 1H) , 7.48 (s, 1H), 7.32 (s, 1H), 7. 14 (s, 1H), 5.38 (s, 2H), 4.31 (m, 4H), 4.25 (m, 2H), 4.11 (m, 4H ), 3.50 (m, 2H), 1.48 (s, 6H), 1.40 (t, J=1.2 Hz, 3H), 1.37 (s, 9H), 1.30 (t, / = 7. 2 Hz, 3H), 1.19 # (t, J = Ί.2 Hz, 3H) Example 32 l-[3-(l-Adamantyl)-4-methoxy-5-morpholinylphenyl]-2-(5,6- Diethoxy-4-fluoro-3-imino-1,1'-dimethyl-isoindolin-2-yl)ethanone hydrobromide

First step 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]-2-(5,6-diethoxy-4-fluoro-3-imine 1,1,1'-dimethyl-isoindolin-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3,3-dimercapto-isoindole哚-Butamine 24d 161 95255 201242964 (266mg, 1mmol) dissolved in 5mL N,N-dimethyl decylamine, added 1-[3-(bumantyl)-4-decyloxy-5-? Phenylphenyl]-2-bromo-ethanone 17h (493 mg, 1. lmmol) was stirred for 12 hours. To the reaction mixture, 20 mL of water and 15 mL of ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with water (10 mL×3) and saturated sodium carbonate solution (10 mL×3), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product 1-[3-(1--------------------- 3-Imino-1,1'-dimethyl-iso-π-bendolin-2-yl)ethanone hydrobromide 32 (40 mg, pale yellow solid), yield: 56%.鲁 MS m/z (ESI): 634 [M+l] *H NMR (400 MHz, DMSO-i/e, ppm): δ 9. 35 (s, 1H), 8.99 {br. s, 1H), 7.61(m, 1H), 7.56(m, 1H), 7.46(s, 1H), 5.46 (s, 2H), 4.26(m, 2H), 4. ll(ra, 2H), 3.96(s, 3H) , 3. 82(ra, 4H), 3. 02(m, 4H), 2. 07(s, 9H), 1.75(s, 6H), 1.50(s, 6H), 1.41(t, /=7.2 Hz , 3H), 1.31 (t, / = 7.2 Hz, 3H) Example 33 1-(8~*tert-butyl-4-ethyl-2,3-dihydro-1,4-benzo. Oxygen 0 Qin -6-yl)_2-(5,6-diethoxy-4-gas-3-imino-1,1-didecyl-iso- 0-bendolin- 2-yl) ethyl ketone hydrobromide Acid salt

162 95255 201242964 First Step 1-(8-tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzo[0--6-yl)-2-(5,6-di Ethoxy-4-fluoro-3-imino-1,didecyl-isoindolebendene-2-yl)ethanone oxime acid salt 5,6--ethoxy-3-didecyl- Dissolve 24d (200mg, 0.75mmol) in 4mL N,N-dimethylformamide, add 2-bromo-1-(8-tert-butyl-4-ethyl-2, 3-Dihydro-1,4-benzoxazin-6-yl)ethanone 6b (282 mg, dec. 83 mmol) was stirred for 12 hours. Φ 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phase was combined, washed with water (1 〇mL×3) and saturated sodium carbonate solution (10 mL×3), dried over anhydrous magnesium sulfate Filtration, the filtrate was concentrated under reduced pressure, ethyl acetate (2 mL) was evaporated, filtered, and filtered and evaporated to give the title product 1-(8-tert-butyl-4-ethyl-2, 3-dihydro-1,4-benzene And 嘹-6-yl)_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-iso- 丨 丨 丨 朵 朵 _2 _2 基 _2 _ _2 _2 _2 Hydrobromide 33 (55 mg, pale yellow solid), yield: ΐ 2 1%. • MS m/z (ESI): 526 [M+l] 4 PiMR (400 MHz, DMSO-form, ppm): δ 9. 23 (eg sa) 8.92 (br. s, 1H), 7.45 (s, 1H ), 7.56 (m, 1H), 7 27 (m 1H), 5.35 (s, 2H), 4.27 (m, 4H), 4. 12 (m, 2H) 3 43 (m, 2H), 3.37 (t, / = 4. 0 Hz, 2H), 1.50 (s, 6H), 1.42 (t, /= 7.2 Hz, 3H), 1.37 (s, 9H), 1.31 (t, /=72 Hz, 3H), 1. 12 (t, / = 6.0 Hz, 3H) Example 34 1-(3,5-di-tert-butyl-4-decyloxyphenyl)-2-(5,6-diethoxy- 4_ gas 95255 163 201242964 -3-Imino-1,1-dimethyl-isoindoline_2~yl)ethanone hydrobromide

The first step is 1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1- Dimethyl-isoindolyl) ethyl ketone oxime bromide 5,6-diethoxy-7-fluoro-3,3-didecyl-isoindole-1-amine 24d (200mg, 0.75 Methyl) was dissolved in 4 mL of N,N-dimercaptocarhamamine and added to 2-bromo-1-(3,5-di-tert-butyl-4-methoxyphenyl)ethanone 21 (:(〇28) g,0. 83 mmol), the reaction was stirred for 12 hours. To the reaction mixture was added 5 mL of water and 5 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (5mL×3), and the organic phase was combined with water (10mL×3) and saturated sodium carbonate solution Wash (丨〇mLx3), dry over anhydrous magnesium sulfate <filter, concentrate the filtrate under reduced pressure, add 2 mL of ethyl acetate, and then dry under vacuo to give the title product 1 -(3,5-di-tert-butyl-4-methyl Oxyphenyl)-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-isoindol-2-yl)ethanone hydrobromide Salt 34 (60 mg, pale yellow solid), Yield: 13.2%. MS m/z (ESI): 527 [M+l] NMR (400 MHz, dUSO-ώ, ppm): δ 9.31 (br. s , 1H), 8.96 (br. s, 1H), 7.93 (s, 2H), 7.45 (s, 1H), 5.43 (s, 164 9 5255 201242964 2H), 4. 27 (m, 2H), 4. 12 (m 2H) q 71 ,

Hz, 3H) 7· L

The first step is 1-(3,5-di-tert-t-t-phenylphenyl)-2-(5,6-diethoxy-4-indolimido-1, bis-indenyl-isoindoline-2-yl Ethylketone hydrobromide salt 5,6-diethoxy-7-fluoro-3,3-dimercapto-isodecylamine 24d (266 mg, 1_〇1) was dissolved in 4 mL of N,N-dioxin 2, bromo-1-(3,5-di-tert-butyl-phenyl)ethanone 22 (: (0.342, 1.1 with 1〇1) was added to the carbamide, and the reaction was stirred for 12 hours. Add 5 mL of water and 5 mL of ethyl acetate, the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with water (10mL×3) and saturated sodium chloride solution (10mL×3), dried over anhydrous magnesium sulfate, filtered, and concentrated. Ethyl ester, filtered, and dried <RTI ID=0.0> 1,1-dimercapto-iso-introduction*»Dol-2-yl)B-argon bromide 35 165 95255 201242964 (7 〇 mg, white solid), yield: 12. 1%. MS m/ z (ESI): 497 [M+l] NMR (400 MHz, DMSO-c/e, ppm): δ 9.37 (k.s.) 8.98 (br. s, 1H), 7.87 (m, 2H), 7.78 (m) , 1H), 7.47 (s, 1H), 5.48 (s, 2H), 4.26 (m, 2H), 4.12 (m, 2 H), 1.52 (s, 6H), 1.42 (t, /= 7.2 Hz, 3H), 1.36 (s, 18H), 1.31 (t, / = 7. 2 Hz, 3H) Example 36 l-[3- tert-Butyl-4-decyloxy-5-(1-piperidinyl) phenyl]-2-(5,6-diethoxy-1,1-diethyl-4-fluoro-3-arylene Amino-isoporphyrin-2-yl)ethanone hydrobromide

First step 3-(3,4-diethoxy-5,fluoro-phenyl)pent-3-ol-5-bromo-1,2-diethoxy-3-fluoro at 78 ° C -Benzene 23e (26.3 g, 0·lmol) was dissolved in 10 mL of diethyl ether, n-butyllithium (44 mL, 0.11 mol) was added, the reaction was stirred for 30 minutes, and 3-pentanone (11.6 mL, 166 95255 201242964) was added. 0. llmol), continue to react for 2 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium carbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified with EtOAc EtOAc (EtOAc) Yield: 74.7%. NMR NMR (400 MHz, CDCh, ppm): δ 6.77 (d, / = 2. 0 Hz, 1H), 6.72 (dd, Ji = 12.0 Hz, 2.0 Hz, 1H), 4.14 (ra> 4H), 1 85 (m, 4H), 1. 47 (t, / = 7. 2 Hz, 3H), i. 4〇(t, / = 7. 2 Hz, 3H), 0. 80 (t, / = 7 6 Hz, 6H) The second step is 5-(1-azido-1_ethyl-propyl)-1,2-diethoxy-3-fluoro-benzene. Under ice bath, 3-(3, 4-Diethoxy-5-fluoro-phenyl)pentan-3-ol 36a (20 g, 0.074 mol) was dissolved in 250 mL of chloroform, sodium azide (14.4 g, 0.22 mol) and Fluoroacetic acid (27. 4 mL, 〇.37 mol), disturbed and reacted for 12 hours. 200 mL of water was added to the reaction mixture, and the mixture was extracted with a methylene chloride (150 mL×2). The combined organic phase was washed with saturated sodium hydrogen carbonate solution (200 mL×5), dried over anhydrous sodium sulfate, filtered, - (1-azido-1_ethyl-propyl)-1,2-diethoxy_3_ gas_benzene 36b (21 _ 2 g, pale yellow oil), yield: 97. 2 %. *H NMR (400 MHz, CDCh, ppm): δ 6.72 (d, / = 2. 4 Hz, 1H), 6. 69 (dd, = 11. 6 Hz, /? = 2. 4 Hz, 1H), 4. 17 (m, 4H), 1.96 (m, 4H), 1.48 (t, /= 7.2 Hz, 3H), 1.40 (t, / = 7. 2 Hz, 3H), 0.82 (t, / = 7. 6 Hz, 6H) 95255 167 201242964 Third step 1-(1-azido-1-ethyl-propyl)-2-bromo-4, 5-diethoxy-3-fluoro-benzene 5--(( 1-azido-1-ethyl-propyl)-1,2-diethoxy-3-fluoro-benzene 36b (21 g, 71.2 mmol) was dissolved in 250 mL of acetic acid, and liquid bromine (7. lmL, 142.3 mmol) and sodium acetate (u. 67 g, 142.3 mmol) were stirred for 144 hours. 250 mL of a saturated sodium sulfite solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of n-hexane and ethyl acetate (V/V = 5:1) (100 mL×3), and the organic phase was combined with a saturated sodium hydrogen carbonate solution (10 mL) The saturated sodium carbonate solution was washed (100 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1-U-azido-1-ethyl-propyl)-2-bromo-4, 5-diethyl 2%。 Oxy-3-fluoro-benzene 36c (24. 1 g, yellow oil), yield: 90.2%. !H NMR (400 MHz, CDCh, ppm): δ 7.12 (d, / = 2. 0 Hz, 1H), 4.16 (in, 4H), 2.69 (m, 2H), 1.97 (m, 2H), 1.48 ( t, /= 7.2 Hz, 3H), 1.41 (t, J = 1.2 Hz, 3H), 0.79 (t, / = 7. 6 Hz, 6H) Step 4 5, 6-Diethoxy-3, 3 -Diethyl-7-fluoro-isoindol-1-amine 1-(1-azido-1-ethyl-propyl)-2-bromo-4, 5-diethoxy-3-fluoro - Benzene 36c (11 g, 29.3 mmol) was dissolved in 1 mL of dimethyl sulfoxide, and cuprous cyanide (5.25 g, 58.7 mmol) and cuprous iodide (5.57 g, 29.3 mmol) were added. The reaction was stirred at 150 ° C for 2 hours. Add 300 mL of water to the reaction mixture. The aqueous phase is extracted with ethyl acetate (400 mL). The organic phase is combined, washed with aqueous ammonia (100 mL), washed with water to blue, and extracted with dilute hydrochloric acid (i〇〇mLx5). And then extracted with ethyl acetate (i 〇〇 mL x 3), combined organic 168 95255 201242964 phase dried anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 5, 6- ethoxy-3. 3-Diethyl-7-fluoro-iso-p- 11-l-amine 36 (1 (2. 24 g, m.). m. M+l] ^ NMR (400 MHz, CDCK ppm): δ 6. 93 (s, 1H), 6.37 (set s, 2H), 4. 12 (d, / - 6. 8 Hz, 2H) , 4. 02 (d, / = 6. 8 Hz, 2H), 1.74 (m, 4H), 1.36 (t, /= 6.8 Hz, 3H), 1.26 (t, / = 6.8 Hz, 3H), 0.46 { Br. s, 6H) Step 5 l-[3-tert-Butyl-4-decyloxy-5-(1-0-carbyl)phenyl]_2-(5,6-diethoxy-1 ,1_diethyl-4-fluoro-3-imino-iso-sigma-proton-2-yl)ethanone hydrobromide 5,6-diethoxy-3,3-diethyl -7-fluoro-isoindol-1-amine 36d (0.3 g, 1 mmol) and 2-di-1-[3-tert-butyl-4-decyloxy-5-(1 -pyrylene) Phenyl ]-Ethylketone 12b (0.4 g, 1.1 mmol) was dissolved in 6 mL of N,N-dimercaptocarbamide and subjected to microwave reaction at 60 ° C for 60 minutes. 5 〇mL of water and 2 mL of saturated sodium hydride solution were added to the reaction solution, and the mixture was filtered, and the filter cake was washed with water (100 mL) and a mixed solvent of hexane and acetic acid (V/V=5:1) (100 mL). The residue obtained by purifying the eluent system A with Shih-Hybrid column chromatography gave the title product 1-[3-tert-butyl-4-decyloxy-5-(1-pyrylene)phenyl] -2-(5,6-diethoxy-1,1-diethyl-4-^-3-imino-iso-brodo-2-yl)ethanone hydrobromide 36 (0.02 g, yellow solid), Yield: 3.0%. MS m/z (ESI): 582 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 7.63 (s, 1H), 7. β〇169 95255 201242964 (s, 1H) , 7.29(s, 1H), 5. 28 (s, 2H), 4.25 (m, 2H), 4.15 (m, 2H), 3. 97 (s, 3H), 2. 99 (m, 4H), 2 . 02 (m, 4H), 1. 57 (m, 4H), 1.43 (m, 2H), 1.34 (m, 15H), 0.45 (t, /= 7.2 Hz, 6H) Example 37 1-(3- tert-Butyl_4-methoxy-5-0pyrrolo*-1-yl-phenyl)-2-(5,6-diethoxy-1,diethyl- 4-fluoro-3- Imino-iso-inducible α-dolin-2-yl)ethanone hydrobromide

The first step is 1-(3-tert-butyl-4-methoxy-5-ηpyrrol-1-yl-phenyl)-2-(5,6-diethoxy_1,1_二Ethyl-4-fluoro-3-imino-iso, °dolin-2-yl)ethanone hydrobromide 5,6-diethoxy-3,3-diethyl-7-fluoro -iso- 0-decyl-1-amine 36d (0.3 g, 1 mmol) and 2-di-1-(3-tert-butyl-4-decyloxy-5-anthracene p -Phenyl)ethanone 8d (0.39 g, 1. lramol) was dissolved in 6 mL of N,N-dimethylformamide, and microwaved at 60 ° C for 60 minutes &quot; 100 mL of water was added to the reaction solution. The solvent mixture was extracted with n-hexane and ethyl acetate (V/V = 5:1) (100 mL), and concentrated under reduced pressure. The obtained residue was purified by eluent column chromatography with eluent system a 170 95255 201242964 to give the title product丨_(3_tert-Butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(5,6-diethoxy-1,1-diethyl_4_fluoro 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. MS m/z (ESI): 568 [M+l] H NMR (400 MHz, DMSO-form, 卯m): § 9·43 (Factory s, a) 9.06 (br. s, 1H), 7.49 ( s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 5. 30 (s, 2H), 4. 27 (q, / = 7 2 Hz, 2H), 4. 15 (q, / = 7. 2 Hz, 2H), 3.67 (s, 3H), 3.20 (m, 4H), 2.05 (m, 4H), 1.94 (m, 4H), 1.40 (s, 9H), 1.33 (m, 6H) , 0.45 (t, J = Ί.2 Hz, 6H) Example 38 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)_2-(5,6-diethoxy -1,1-diethyl-4-fluoro-3-imino-isoporphyrin-2-yl)ethanone hydrobromide

First step 1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)-2-(5,6-diethoxy-1,diethyl-4-fluoro-3 -imino-isoindoline-2-yl)ethanone hydrobromide 95255 171 201242964 5,6-diethoxy-3,3-diethyl_7~gas-iso-n n- Ig-amine 36d (0.3 g, lmm〇i) and 2-bromo-1-(3-tert-butyl-4-methoxy-5-?'#phenyl)ethanone 2h (0.41 g, 1 .lmmol) dissolved in 6 mL of N,N-dimethylamine, '6 (TC microwave reaction for 60 minutes. Add 100 mL of water to the reaction solution with n-hexane and ethyl acetate (V/V = 5:1) The solvent mixture (100 mL) was concentrated under reduced pressure. The obtained residue was purified eluting from EtOAc EtOAc EtOAc Linphenyl)-2-(5,6-diethoxy-1,1-diethylfluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide 38 (0.02 g, yellow solid), Yield: 2% MS m/z (ESI): 568 [M+l] H NMR (400 MHz, DMSO-i/6, ppm): δ 9.48 (Z?/*. s ,1H), 9. 10(Z?r. s, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7. 32 (s, 1H), 5. 35 (s, 2H), 4 . 27 (q, / = 7. 2 Hz, 2H), 4. 14 (q, /=7. 2 Hz, 2H), 3.97 (s, 3H), 3.84 (in, 4H), 3.05 (m, 4H), 2.00 (m, 4H), 1.39 (s, 9H), 1.33 (m, 6H) ), 0.52 (t, / = 7. 2 Hz, 6H) Example 39 [3-tert-butyl-4-decyloxy-5-[(1 foot 5Λ-8-oxa-3-azabicyclo) [3.2.1] Oct-3-yl]phenyl]-2-(5,6-diethoxy_4-oxa-3-imino-1,1-dimercapto-isoindoline- 2-yl) ethyl ketone hydrobromide 172 95255 201242964

The first step [(2 feet 5 magic-5-(methyl)tetrahydrofuran-2-yl] decyl alcohol 1,5-hexadiene 39a (4.6g, 56_υ dissolved in 6 wins four

In the mixed solvent of =, add high molybdate · g' 123 to remove 1) ‘ three gasification seals (23, 〇. Uram〇i), 8〇 g two and called the mixing reaction for 8 hours. The reaction solution was concentrated under reduced pressure, and then added, / /, &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& -5-(sulfonyl) tetrahydrosevenan, 2 benzyl] sterol liquid), yield: 58.6 %. g,*''' 4 NMR (400 MHz, CDC13, ppm): δ 4. 08 (m, 2H), 3. 76 (m 2H), 3.73 (m, 4H), 1.92 (in, 2H), 1.79 (m, 2H) The second step 95255 173 201242964 [(2 especially 5»S)-5-(p-toluene continuous oxoyl)-tetrahydron-pentan-2-yl]-methyl-4-indenyl Benzene acid is prepared by dissolving [(2 especially 55)-5-(hydroxymethyl)tetrahydrofuran-2-yl]methanol 39b (3·Og, 22.7 mmol) in 20 mL of di-methane and adding 4-toluenesulfonate. Gas (8.6 g, 45.4 mmol) and pyridine (4.4 mL, 54.5 mmol) were stirred for 12 hours. 30 mL of water was added to the reaction solution, and the aqueous phase was extracted with trichloromethane (20 mL×3). The combined organic phases were washed with saturated sodium carbonate solution (20 mL×2) and saturated sodium chloride solution (2 mL×2), dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallised from ethanol to give the title product [^ 左^ 幻 巧 曱 曱 曱 醯 醯 醯 醯 醯 四 四 四 四 四 四 四 曱 曱 曱 曱 曱 曱 曱 曱Benzobenzenesulfonate 39c (6.0 g, white solid), yield: 60.0%. Η R (400 MHz, CDCla, ppm): δ 7. 79 (d, */= 8.0 Hz, 4H), 7. 36 (d, / = 8. 0 Hz, 4H), 4. 11 (m, 2H), 3. 94 (m, 4H), 2.46 (s, 6H), 1.95 (m, 2H), 1.72 (m, 2H)

The third step I (1 especially 550-3-benzyl-8-oxa-3-azabicyclo[3.2.1]octane will [(2^ 550-5-(p-toluenesulfonyloxymethyl) ) tetrahydrofuran-2-yl]-mercapto-4-methylbenzenesulfonate 39c (; 4. lg, 9.32 mmol) and benzylamine (3.66 mL, 32.6 mmol) are dissolved in 40 benzene. I2 (TC stirring reaction for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product (1 </ br> 3-Azabicyclo[3.2.1]octane 39d (1.58 g, colorless liquid), Yield: 83.6 %. 174 95255 201242964 4 匪R (400 MHz, CDC13, ppm): δ 7. 32 ( m,5H), 4. 28 (m, 2H), 3.47 (s, 2H), 2.56 (d, /=12. Hz, 2H), 2.36 (d, /= 12.0 Hz, 2H), 2.01 (m , 2H), 1.99 (m, 2H) The fourth step (1^ 5/?)-8-oxa-3-azabicyclo[3. 2. 1 ] 辛烧(1 尤55)-3-benzyl Base-8-oxa-3-azabicyclo[3.2.1]octane 39d (1.5 g, 7.39 mmol) was dissolved in 200 mL of ethyl acetate. Palladium/carbon (75 mg, 5%) was added. The hydrogen was replaced three times, and the reaction was stirred at 80 ° C for 2 hours. The counter solution was concentrated under reduced pressure, and the filtrate was filtered and concentrated under reduced pressure to give The title product (15; 5 Λ 0-8-oxa-3-azabicyclo[3. 2. 1 ] 辛院 39e (347 mg, colorless liquid), yield: 83.3 % MS m/z (ESI): 114 [M+l] Step 5 1-[3-tert-Butyl-4-methoxy-5-[(1 especially 5S)-8-oxa-3-azabicyclo[3. 2·1] Oct-3-yl]phenyl]ethyl _ 1 - tert-butyl 5 (1,1-monodecyloxyethyl)-3-position-2-methoxyphenanthene 2f (761 mg, 2. Olnunol) and 2-Dicyclohexylphosphino 2'-(N,N-dimethylamine)-biphenyl (79 mg, 0.20 mmol) was dissolved in 1 Torr of toluene and added / carbon (76 mg, 10%), tert. Potassium alkoxide (786 mg, 7. 00 mmol) and (is, 5 kg) ~ 8 oxa-3-azabicyclo[3. 2. 1]octane 39e (228 rog, 2. 01_〇1), 80 ° C The reaction was stirred for 5 hours. 2 mL of water was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phase was combined, washed with saturated sodium carbonate solution (10 mL) dried over anhydrous sodium sulfate, filtered, filtrate reduced Concentration by pressure, addition &amp; acetic acid and 1 mL of water were added, and the reaction was stirred for 1 hour. 2 mL of water was added, and the aqueous phase was extracted with 2 95255 175 201242964 ethyl acetate (5 mL×3). The organic phase was combined, washed with saturated sodium sulfate solution (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated. Column chromatography Chromatography of the obtained residue to afford the title product 1-[3-tert-butyl-4-decyloxy-5-[(1 br. Bicyclo[3.2.1] oct-3-yl]phenyl]ethanone 39! (28611^, yellow solid), Yield: 45.0%. MS m/z (ESI): 318 [M+l] H NMR (400 MHz, CDCh, ppm): δ 7.67 (d, / = 2. 0 Hz, 1H), 7.52 (d, /= 2.0 Hz, 1H), 4.44 (m, 2H), 3.94 (s&gt; 3H ), 3. 17 (d, / = 12. 0 Hz, 2H), 3. 01 (d, /= 12. 〇Hz, 2H), 2.57 (s, 3H), 2.12 (m, 2H), 2.05 ( m, 2H), 1 41 (s, 9H) Step 6 2-Bromo-l-[3-tert-butyl-4-decyloxy-5-[(l and, 55*)-8-oxa- 3-Azabicyclo[3. 2·1]oct-3-yl]phenyl]ethanone 1-[3-tert-butyl-4-methoxy-5-[(1疋) at 40 ° C 5«-8-oxa-3-azabicyclo[3. 2·1]oct-3-yl]-phenyl]-ethanone 39f (258 mg, 0.81 mmol) was dissolved in 8 mL of chloroform and brominated Copper (363. 6g, 1. 63 〇1), stir The reaction was stirred for 12 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by eluent column chromatography using eluent column chromatography to give the product 2-bromo-l-[3-tert-butyl-4-methyl Oxy-5-[(100 million 550-8-oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]ethanone 39 light (22〇11^, yellow solid) Rate: 68.3%. !H NMR (400 MHz, CDCh, ppm): δ 7.70 (d, / = 2. 4 Hz 176 95255 201242964 1H), 7.55 (d, /= 2.4 Hz, 1H), 4.45 ( m, 2H), 4.40 (s, 2H), 3.96 (s, 3H), 3. 17 (d, /= 12.0 Hz, 2H), 2.99 (d, /= 12. 0 Hz, 2H), 2. 12 (m, 2H), 2. 05 (m, 2H), 1. 41 (s, 9H) Step 7 l-[3-tert-Butyl-4-decyloxy-5-[(l especially 5«- 8-oxa-3-azabicyclo[3·2·1]oct-3-yl]phenyl]-2-(5,6-diethoxy-4-fluoro-3-iminoamino-1 , 1_ monomethyl-iso-° lead-to-trace 2 ~~ base) B, the same gas desert acid salt, 5, 6--ethoxy-7-fluoro-3, 3-dimethyl-iso-di -1 -amine 24d (189 mg, 0.71 mmol) and 2-bromo-l-[3-tert-butyl-4-decyloxy-5-[(1 especially 55)-8-oxa-3-aza Bicyclo[3. 2. 1]oct-3-yl]-phenyl]ethanone 39g (310mg, 0.78mmol) was dissolved in 5mL of N,N-dimethyl Amines, granted stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with saturated sodium sulfate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to give the title product [3-tert-butyl-4-decyloxy-5-[(U5l9)-8, oxa-3, azabicyclo[3·2· U xin-3% Phenyl 2_(5'6-diethoxylated_4_fluoro_3_imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 3%。 The acid salt 39 (72 mg, yellow powder), yield: 15.3%. ' MS m/z (ESI): 582 [M+l] 4 NMR (400 MHz, DMSO-form, ppm): δ 9.35 (eg s 1H) 8.97 {br. s, 1H), 7.62 (m, 2H) , 7.46 (s, 1H), 5. 45 (s, 2H), 4. 41 (m, 2H), 4.24 (q, / = 7. 2 Hz, 2H), 4. 13 (q, 95255 177 201242964 / = 7. 2 Hz, 2H), 3.92(s, 3H), 3. 12 (m, 2H) 2 〇qr 2H), 2.07(m,2H), h92(m,2H),i 5〇(s ' U9(m, (t, /= 7.2 Hz, 3H), 1.39(S, 9H), };

Hz, 3H) 5 7 = 7. 2 , tert-butyl + methoxy co-oxa + oxaspiro[3.3-yl) benzyl]-2-(5, 6-diethoxy _4 Amine 4, oxaisoin-2-yl)ethanone hydrobromide

The first step 2-(p-benzoquinone hydrazino oxa-2-azaspiro[33]heptane will be 3 / odor ~ 2, 2 - 2 (methanol) propane-bupropanol 40a (65. Og 〇 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20遽, the filter cake was washed with ethanol (10 mL×3), true 178 95255 201242964, and dried to give the title product 2-(p-phenylenesulfonyl)-6-oxa-2-azaspiro[3.3]heptane 40c (30_Og, white solid), Yield: 59.2%. MS m/z (ESI): 254 [M+l] 4 NMR (400 MHz, CDC13, ppm): δ 7. 71 (d, 8.0 Hz, 2H), 7. 14 (d, / = 8· 0 Hz, 2H), 4. 59 (s, 4H), 3. 91 (s, 4H), 2.44 (s, 3H) Step 6 - Oxa-2-azaspiro[3.3]heptane oxalate 2-(p-phenylenesulfonyl)-6-oxa-2-azaspiro[3,3]heptane 40c (5 5g, 22. Ommol) was dissolved in 120 mL of methanol, magnesium powder (42 g, 174 mmol) was added, and the mixture was subjected to ultrasonic reaction for 1 hour. Concentrated under reduced pressure, and added with 18 〇 of the mixture and 30 g of sodium sulfate dehydrate. , transition, add 5mL of 1M oxalic acid in ethanol solution to the tears, stir 5小时,白固体固体。 5 hours, the transition, the tear cake was washed with ethanol (10mLx3) 'vacuum dried to give the title product 6_oxa-2-azaspiro[3.3] gypsum oxalate 40d (2.6 g, white solid ), yield. 74. 20 / 〇 MS m / z (ESI): 100 [M + l] The third step l-[3-tert-butyl 1-4-decyloxy-5-(6-oxygen) Hetero-2-azaspiro[3. 3]heptan-2-yl)phenyl]ethanone 1-tert-butyl-5-(1,1-dimethoxyethyl)-3-iodine 2-Methoxybenzene 2f (8.5 g, 23 mmol) and 2-dicyclohexylphosphino-2,-(N,N-dimethylamine biphenyl (443 mg, 1.13 mmol) were dissolved in 12 mL of a stupid, Add palladium/stone (850 mg, 10%), potassium t-butoxide (7.6 g, 68 mmol) and oxa 1 nitrogen 95255 179 201242964 heterospiral [3.3] glycolate oxalate 4 〇 d (9. 0 g, 25_〇1), the reaction was stirred for 1 hour at 60 ° C. 200 mL of water was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed with saturated sodium carbonate solution (5 mL) The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. &lt;1&gt; 2 mL of water was added, and the aqueous phase was extracted with ethyl acetate (5 〇mL×3). The organic phase was combined, washed with saturated sodium carbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained was purified by eluent column chromatography to afford the title product 1-[3-tert-butyl-4-methoxy-5-(6-oxa-2-azaspiro[3. 3]heptan-2-yl)phenyl]ethanone 40e (6.0 g, gray solid), yield: 88.2%. MS m/z (ESI): 304 [M+l] 4 丽 R (400 MHz, CDCI3, ppm): δ 7.46 (d, /= 2.0 Hz, 1H), 7. 05 (d, / = 2. 0 Hz, 1H), 4. 85 (s, 4H), 4. 02 (s, 4H), 3.70 (s, 3H), 2.56 (s, 3H), 1.41 (s, 9H) Step 4 2-Bromo- L-[3-tert-Butyl-4-decyloxy-5-(6-oxa-2-azaspiro[3. 3]heptan-2-yl)phenyl]ethanone at -78 ° C , bis(trimethylsulfonium)amine lithium (12.7 mL, 12.7 mmol;) and 1-[3-tert-butyl1-4-methoxy-5-(6-oxa-2-nitrogen Heterospiral [3.3] heptane~2-yl)phenyl]ethanone 40e (3.5 g, 11.6 mmol) was dissolved in 50 mL of tetraoxo-pyrene, and the reaction was allowed to react for 1 hour. 85 g, 11. 6 mmo 1), stir the reaction for 2 hours. 30 mL of water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (1 mL mL), dried over anhydrous sodium sulfate 180 95255 201242964 Hose column chromatography with eluent system B to purify the resulting product 2-m-tert-butyl+methoxy_5_(6_氡fin[3.3]heptan-2-yl)phenyl]ethanone 4 (^(820, yellow solid), Yield: 18.6%. MS m/z (ESI): 383 [M+l] !H NMR (400 MHz, CDCh, ppm): δ 7. 49 (d , / =2 4 Hz 1H), 7.07 (d, /= 2.4 Hz, 1H), 4.85 (s, 4H), 4.41 (s, 2H), 4.02 (s, 4H), 3.71 (s, 3H), 1.40 (s, 9H) ^ The fifth step l-[3-tert-butyl-4-decyloxy-5-(2-oxa-6-azaspiro[3. 3]hexa-6-yl)] -2-(5,6-diethoxy-4-fluoro-3-iminoamino-1,i-didecyl-iso-decyl)-ethyl ketone hydrogenate ,6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24 (1 (132 mg, 0.50 mmol) and 2-di-l-[3-tert-butyl- 4-decyloxy-5-(6-oxa-2-azaspiro[3. 3]heptan-2-yl)phenyl]ethanone 4〇f (l90mg, φ 〇. 50 〇 1) Dissolved in 2mL of tetrahydrofuran, Triethylamine (1 mL, 0.72 mmol) was added, and the reaction was stirred for 12 hr. filtered, filtered, washed with hexane (1 mL) and water (10 mL×3) Oxy-5-(2-oxa-6-azaspiro[3. 3]hex-6-yl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-arylene Amino-1,1-dimercapto-isoindolin-2-yl)ethanone hydrobromide 40 (15 mg, yellow solid), yield: 6%. MS m/z (ESI): 567 [M+l] JH NMR (400 MHz, dUSO-ώ, ppm): δ 8.99 (br. s, 1H), 7. 45 (s, 2H), 7. 13 (s, 1H), 5. 42 (s, 2H), 4. 71 (m, 4H), 181 95255 201242964 4.25 (q, /= 7.2 Hz, 2H), 4.13 (q, / = 7 2 Hz, 2H), 4. 09 (m, 4H ), 3.67 (s, 3H), 1.50 (s, 6H), 1.41 (t, / = 7. 2 Hz, 3H)' 1. 38 (s, 9H), i 31 (t, / = 7 2 Hz, 3H) Example 41 (3-tert-butyl-4-methoxy~5-mlene phenyl)_2_(5,6, _diethoxy- 4' _ gas_3, _ Amine, [cyclopropan-1,1,-iso-dolin]-2,-yl)acetamidine hydrobromide

First Step 6 &gt; Odor-3, 4-Ethoxy-2-Fluorobenzoic Acid 5-Bromo-1,2-diethoxy-3-fluoro-benzene 23e (15.38g, 58 5mmol) dissolved in 250mL of trifluoroacetic acid, added hexamethylenetetramine (i6.4g, 117mmol), stirred for 30 minutes, 9 (TC continued to react for 5 hours. Add 500mL of water to the reaction solution, with acetic acid Ester extraction (25〇fflLx2), combined with 182 95255 201242964 machine phase, washed with saturated sodium bicarbonate solution (250mLx5), water (200mL) and saturated sodium chloride solution (200mL), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting from EtOAc EtOAc EtOAc EtOAc , yellow solid), yield: 46.30 / 〇 Ή NMR (400 MHz, CDCh, ppm): δ 10.25 (s, 1H), 7. 〇〇 (d, /= 1.6 Hz, 1H), 4.20 (m, 4H), 1.54 (t, / = 7.2 Hz, 3H), 1.43 (t, / = 7.2 Hz, 3H) #第二步6_漠_3, 4-Diethoxy-2-fluoro-benzoic acid [6-Bromo-3, 4-diethoxy-2-fluoro-clavuraldehyde 41a (5.5 g, 18.8 mmol) was dissolved in 50 mL of tetrahydrofuran under ice bath, plus 5 〇 this water, sodium hydroxide (1.2g, 30. lramol) and potassium permanganate (3.28g, 20 7mmol) were reacted at room temperature for 12 hours. Filtration 'filtrate concentrated under reduced pressure, extracted with acetic acid (150mLx3) The 'combined organic phase' was washed with a saturated sodium chloride solution (1 hr) φ dry over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 6 bromo-3, 4-diethoxy-2-fluoro - benzoic acid 41b (3.8 g, yellow solid), Yield: 65. 8%. ' MS ra/z (ESI): 307 [Ml] !H NMR (400 MHz, CDCh, ppm): δ 13. 74 (Z&gt;r ς , , s, iti), 7. (s,1H)' 4.13 (q,/= 7.2 Hz, 2H), 4.05 (q, / = 7 2

Hz, 2H), 1.34 (t, /= 7.2 Hz, 3H), 1.25 (t, J=1 Hz, 3H) ' · Third step 95255 183 201242964 6-Bromo-3, 4-diethoxy-2 -Fluoro-benzoic acid oxime ester 6-bromo-3,4-diethoxy-2-fluoro-benzoic acid 411) (3.8 舀, 12. 4 匪〇 1) was dissolved in 30 mL of nitrous oxide. Reflux for 5 hours. The mixture was concentrated under reduced pressure, and a mixed solution of 45 mL of decyl alcohol and dichloromethane (V/V = 2:1) was added in an ice bath, and the mixture was stirred at room temperature for 12 hours. The title product, 6-bromo-3, 4-diethoxy-2-fluoro-benzoic acid hydrazine s, 41c (3. 46 g, yellow oil), yield: 86.9%. !H NMR (400 MHz, CDCh, ppm): δ 6.90 (d, / = 2. 0 Hz, 1H), 4. 10 (ra, 4H), 3. 94 (s, 3H), 1. 46 (t , J = 1.2 Hz, 3H), 1.36 (t, J = 1.2 Hz, 3H) Step 4 6-Cyano-3, 4-diethoxy-2-fluoro-benzoic acid oxime ester 6-bromo- 3, 4-diethoxy-2-fluoro-benzoic acid oxime ester 41c (3. 46 g, 10-8 mmol) was dissolved in 50 mL of N,N-dimercaptocarbamide, and copper cyanide was added in sequence (2.99). g, 32. 3mmol) and lmL ° bite, 150. The reaction was stirred for 3 hours. The reaction mixture was added with 300 mL of water, filtered, and extracted with ethyl acetate (100 mL×3). The organic phase was combined, washed with water (2 mL) and saturated sodium carbonate solution (200 mL), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAc EtOAc EtOAc (EtOAc) g, white solid), yield: 52.1%. H NMR (400 MHz, CDCh, ppm): δ 7.08 (d, /= 1.2 Hz 1H), 4.27 (q&gt; /= 7.2 Hz, 2H), 4.19 (q, / = 7. 2 Hz, 2H), 4.03 (s, 3H), 1.54 (t, / = 7. 2 Hz, 3H), I.43 (t 95255 184 201242964 J = ΊΛ Hz, 3H) Step 5 5',6'-Diethoxy-7 '-Fluoro-spiro[cyclopropane-indole, 3, _isoindoline dip, ketone ice bath, 6-cyano-3, 4-diethoxy-2-fluoro-benzoic acid The ester 41d (2.66g, 9.96mmol) was dissolved in 30mL of diethyl ether, and tetraisopropyl vinegar titanate (3.3mL, ll.lmmol) and ethyl magnesium bromide (7.3mL, 2i.9mmol) were added to the reaction. 2. 5 hours. 65 mL of decyl alcohol was added to the reaction mixture, and the obtained residue was purified by eluent column chromatography using eluent column chromatography to give the title product: 5',6'-diethoxy-7'-fluoro-spiro[ring Propane-1,3, _isoporphyrin]-;^-ketone 41e (1·48 g, yellow solid), yield: 56. 〇%. MS m/z (ESI): 266 [M+l] 4 丽 R (400 MHz, CDCI3, ppm): δ 8· 02 (s, 1H), 6. 25 (s, 1H), 4. 12 (m , 4H), 1. 63 (m, , 2H), 1.48 (t, /= 7. 2 Hz, 3H), 1.38 (t, /= 7.2 Hz, 3H), 1.35 (m, 2H) Step 6 5',6' _Diethoxy-7' - snail [cyclopropene ~1, 3'-iso n 引 α朵淋]-1' - thioketone 5',6'-diethoxy- 7'-Fluoro-spiro [cyclopropane-1,3,-iso. Tobacco was prepared by dissolving in a 4 mL mL of tetrahydrofuran, and adding a Lawson's reagent (734 mg, 1.81 mmol) at 50 °c for 12 hours. 50 mL of saturated carbonic acid unsalted solution and 40 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phase was combined, washed with saturated sodium sulfate solution (50 mL), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure, and the residue obtained from 185 95255 201242964 was purified by eluent column chromatography to give the title product 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane]. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. MS m/z (ESI): 282 [M+l] *H NMR (400 MHz, CDCh, ppm): δ 9.68 (s, 1H), 6.24 (s, 1H), 4.14 (m, 4H), 1.89 ( m, 2H), 1.52 (m, 2H), 1.49 (t, / = 7.2 Hz, 3H), 1.39 (t, J = 1.2 Hz, 3H) Step 7 5',6'-Diethoxy-7 '-Fluoro-spiro[cyclopropane-1,3'-isoindoline]-oxime-imine 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1, 3, -Isoporphyrin]-Γ-thione 41f (300 mg, 1.07 mmol) was dissolved in 30 mL of methanol, and added 121111 (28% concentrated water and tert-butyl peroxide) (〇.61111 (,6111111〇) 1), the reaction was allowed to react for 12 hours. The reaction solution was concentrated under reduced pressure, and then, i.sub.2 mL of 2M hydrochloric acid and 80 mL of water was washed with ethyl acetate (30 mL×3), and the aqueous phase was adjusted to pH &gt;7 with 5 mL of 5 M sodium hydroxide solution. The mixture was extracted with EtOAc (3 mL, EtOAc) -7,-Gas-spiro [cyclopropane-1,3'-isoindoline]-indole-imine 41 g (147 mg, gray solid), yield: 521. 1%. 265 [M+l] Ή NMR (40 0 MHz, CDCh, ppm): δ 6. 71 (s, 1H), 6. 10 {br s, 2H), 4. 09 (q, / = 7. 2 Hz, 2H), 4. 01 (q, /= 7. 2 Hz 2H), 1.49 (m, 2H), 1.42 (m, 2H), 1.35 (t, / = 7. 2 Hz 95255 186 201242964 3H), 1. 26 (t, / = 7. 2 Hz, 3H) Step 8 1-(3-tert-Butyl-4-decyloxy-5-morpholinylphenyl)_2_(5,6,-diethoxy-4'-fluoro-3' - Imino-spiro[cyclopropane-1, hydrazine, -isoporphyrin]_2,-yl)ethanone hydrobromide salt 5',6'-diethoxy-7,-fluoro-spiro[ring Propane-1,3,-isoindoline]-1'-imine 41g (184mg, 〇. 7mmol) and 2-bromo-b (3-tert-butyl-4-decyloxy-5-morpholin benzene Ethyl ketone 2h (370 mg, 0.7 mmol) was dissolved in 6 mL of THF, triethylamine (0. 15 mL, 1.08 mmol) was added, and the reaction was stirred for 12 hours. Filtration, the filter cake was washed with n-hexane (1 mL) and water (10 mL×3) and dried in vacuo to give the title product 1-(3-tert-butyl-4-yloxy-5-m-phenylene-2-)-2- (5',6'-diethoxy-4'-fluoro-imino-spiro[cyclopropane-1, hydrazine-isoindoline] 2,-yl) ethyl ketone hydrobromide 41 (52 mg, 8%。 The white powder), the yield: 11.8%. MS m/z (ESI): 554 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9. 35 (々rs iH) 9.06 (&amp;. s,1H), 7.62 (d, 2.0 Hz, iH), 7, 53 (d 2.0 Hz, 1H), 7.03 (s, 1H), 5.22 (s, 2I1), 4 24 (q /= 7.2 Hz, 2H)' 4.13 (q, 7.2 HZ, 2H), 3.96 (s' 3H), 3.82 (m, 4H), 3.02 (m, 4H), 1.80 (m, 2H), i 66 (m, 2H), 1.40 (t, /= 7.2 Hz , 3H), 1.38 (s&gt; 9H) 1 31 (t, / = 7. 2 Hz, 3H) Example 42 95255 187 201242964 1-(3, 5-di-tert-butyl-4-hydroxyphenyl)_2_( 5,6, _diethoxy- 4'-fluoro-3'-imino-spiro[cyclopropane-indole, hydrazine, _isoporphyrin]_2, yl) ethyl ketone hydrogen

Bromate first step 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6, _diethoxy-4, _fluoro-3'-imino -spiro[cyclopropane-oxime, 丨' _isoporphyrin]_2, _yl) ethyl ketone oxime bromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane_丨,3,-isoporphyrin]-1' _imine 41g (2〇lmg, 0·76mmol) and 2-bromo-bu (3, 5-di-tert-butyl-4-hydroxyphenyl)ethanone if (327 mg, 0.87 mmol) was dissolved in 6 mL of tetrahydrofuran, triethylamine (15 mL, 1 〇8_〇1) was added, and the reaction was stirred for 12 hours at 30 ° C for 48 hours. Filtration, the cake was washed with n-hexane (10 mL) and water (1 mL) and dried in vacuo to give the title product 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5, 6,-diethoxy_4, _fluoro-3-imino-spiro[cyclopropane-1,1'-iso-ηbendolin]__2, __yl)ethyl-hydrobromide 42 (67 mg, white powder), yield: 14.7%. MS ra/z (ESI): 511 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.06 (br s 2H) 95255 188 201242964

7.77 (s, 2H), 7.03 (s, 1H), 5.27 (s, 2H), 4.23 (q, J =7· 2 Hz, 2H), 4. 12 (q,/= 7. 2 Hz, 2H) , 1.78 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (t, /=7. 2 Hz, 3H), 1. 31 (t, / = 7. 2 Hz , 3H) Example 43 2-[8-tert-Butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane- 1, Γ - iso n bow buddin] _2 '-yl) ethyl aryl]-2, 3-dihydro-1,4-benzo-oxazin-4-yl] ethyl acetate hydrobromide

First step 2-[8-tert-butyl-6-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, hydrazine] -isoindole D Ding]-2'-yl)ethinyl]-2,3-dihydro-1,4-benzo[poxazin-4-yl]acetic acid ,6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3'-isoindole-l-alendene]-1'-imine 418 (121111£, 0.46111111〇1) and 2- [6-(2-Molybdenyl)-8-tert-butyl-2,3-dihydro-1,4-benzoxanthazine~4~yl]acetate acetal 5e (201mg, 0.50mmol) dissolved Triethylamine (0.1 mL, 0.72 mmol) was added to 4 mL of THF. After overhaul, the cake was dried with vacuum (10 mL) and washed with water (l〇ffl Lx3). Vacuum dried to obtain the product of 95255 189 201242964 2-[8-tert-butyl-6-[2-(5',6' -diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1, Γ-iso- 0 引 ° 朵 · ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] - dihydro-1,4-benzoxazin-4-yl]ethyl acetate hydrobromide 43 (147 mg, yellow powder), yield: 48.4%. MS ra/z (ESI): 583 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 9.72 (br. s, 1H), 9. 18 {br. s, 1H) , 7. 30 (s, 1H), 7. 13 (s, 1H), 7. 06 (s, 1H), 5.33 (s, 2H), 4.31 (s, 2H), 4.29 (m, 2H), 4.23 (q, 7.2 Hz, 2H), 4.11 (m, 4H), 3.49 (m, 2H), 1.74 (ra, 2H), 1.65 (m, 2H), 1.39 (t, / = 7.2 Hz, 3H), 1.36 (s, 9H), 1.30 (t, J = 1.2 Hz, 3H), 1.19 (t, / = 7. 2 Hz, 3H) Example 44 _(3, 5-di-tert-butylphenyl)-2- (5,6, _diethoxy_4, pu 3,-imino-snail [cyclopropanone-U'-iso, Duo Lin]-2,-yl) ethyl ketone hydrogenate

1-(3,5-di-tert-butylphenyl yz-G, aminyl-spiro[cyclohexyl]diethoxy-4'-fluoro-3, a sub-5,6,-diethoxy Base one, 7, turtle, ], 2_ base) 乙明氢化盐1, snail [cyclopropan-1,3,-iso η 弓 朵 19 19 95255 201242964 琳]-Γ-imine 41g ( 132 mg, 0.5 mmol) and 2-di-b (3,5-tert-butyl-phenyl)ethanone 22c (178 mg, 0.57 mmol) were dissolved in 4 mL of tetrahydrofuran 'Addition of triethylamine (〇·lmL, 〇.72 mmol) The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (i.sub.mL) and water (i.sub.3×3) and dried in vacuo to give the title product 1-(3,5-di-tert-butylphenyl)-2- (5',6' -diethoxy-4'-fluoro-3,-imino-spiro[cyclopropane-oxime, hydrazine, _isoporphyrin]-2'-yl) ethyl ketone hydrobromide 44 (54 mg, white 8%。 The yield: 18.8%. _ MS m/z (ESI): 495 [M+1] R R (400 MHz, DMSO-i/e, ppm): δ 9.38 (6/* s iH) 9.05 (br. s, 1H), 7.82 (d, /= 1.6 Hz, 2H), 7.78 (d / = 1. 6 Hz, 1H), 7. 03 (s, 1H), 5. 25 (s, 2H), 4. 24 (q /= 7.2 Hz, 2H), 4.13 (q, / = 7. 2 Hz, 2H), 1.83 (m 2H), 1.67 (m, 2H), 1.41 (t, /= 7. 2 Hz, 3H) 1 36 (s 18H ), 1.31 (t, /= 7.2 Hz, 3H) ' · Example 45 1 -(3,5-di-tert-butyl-4-decyloxy)_2_(5,6, _diethoxy

Ketone hydrobromide

95255 191 201242964 First step 1-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(5',6,-diethoxy-4'-fluoro-3'-Asia Amino-spiro[cyclopropane_丨, 丨, _isoporphyrin]_2,-yl)ethanone hydrobromide 5,6-ethoxy-7,-fluoro-spiro[cyclopropyl- 1,3'-iso-D D-porphyrin]-indole-imine 41g (147mg, 0.56mmol) and 2-bromo-1-(3,5-di-tert-butyl-4-decyloxyphenyl) Ketone 21c (198 mg, 0.58 mmol) was dissolved in 4 mL of tetrahydrofuran, triethylamine (〇.lmL, 〇. 72mm 〇i) was added, and the reaction was stirred at 25 ° C for 12 hours. Filtration of the 'filter cake with n-hexane (1 mL) and water (10 mL x 3) 'vacuum dried' to give the title product i_(3,5-di-tert-butyl-4-yloxyphenyl)-2-(5', 6'-Diethoxy-4,-fluoro-3'-imino-spiro[cyclopropan-1, Γ-isoindoline]-2'-yl)ethanone hydrobromide 45 (47mg 9%。 White powder), yield: 13.9%. MS m/z (ESI): 525 [M+l] H NMR (400 MHz, MSO-ώ, ppm): δ 9.67 (br. s, 1H), 9. 12 (Z?r. s, 1H), 7.90 (s, 2H), 7. 04 (s, 1H), 5. 38 (s, 2H), 4.23 (q, J = 1.2 Hz, 2H), 4.11 (q, / = 7. 2 Hz, 2H) , 3.70 (s, 3H), 1.79 (m, 2H), 1.64 (m, 2H), 1.43 (s, 18H), 1.40 (m, 6H) Example 46 1-(3-tert-butyl-4-indole Oxy-5-pyrrolidin-1-yl-styl)-2-(5,6,-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane_ι,1 ,_吲哚吲哚琳]-2'-base) B_hydrogen desert salt 95255 192 201242964

46 HBr Ο

First step 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)_2_(5',6, mono-diethoxy-4'-fluoro_3 ,-Imino-spiro[cyclopropan-u,-iso-fololine]-2'-yl)ethanone hydrobromide salt 5,6-diethoxy_7'-fluoro-spiro[ring Propane _13, _isoporphyrin]-1 -imine 41g (16 〇 mg, 〇.56 mmol) and 2-bromo-1-(3-tert-butyl-4-methoxy-5-t each -1 -Phenyl-phenyl)ethanone 8d (3 〇lmg, 〇. 58mm 〇1) was dissolved in 4 mL of tetrahydrofuran, added with 1 mL of triethylamine, 〇72 mm 〇1), and stirred at 25 C for 12 hours. Filtration, the filter cake was washed with n-hexane (1 mL) and EtOAc (EtOAc) (EtOAc) —phenyl)_2_(5',6,_diethoxy_4, _fluoro-3'-imino-spiro[cyclopropane-1,1,-isoporphyrin;]-2' _ group 5%。 The same as the hydrobromide 46 (118 mg, white powder), the yield: 31. 5%. MS m/z (ESI): 538 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.36 (br. s, 1H) 9.06 (br. s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.05 (s&gt; 1H), 5.24 (s, 2H), 4.24 (q, / = 7. 2 Hz, 2H), 4.12 (q, /=7. 2 Hz, 2H ), 3. 18(m, 4H), 1.93 (m, 4H), 1.80 (m 95255 193 201242964 2H), 1.66 (m, 2H), 1.40 (t&gt; / = 7 2 Hz, 3H), 1.36 (s , 9H), 1. 31 (t, / = 7. 2 Hz, 3H) Example 47 l-[3-(l-adamantane)-4-decyloxy-morpholinephenyl]_2_(5,, 6, _diethoxy-4-fluoro-3'-imino-spiro[cyclopropanone], Γ_ 异十朵琳]_2'_ base) B-hydrobromide

First step 1-[3-(1-adamantane)-4-methoxy-5-morpholinylphenyl]_2-(5,6,-diethoxy-4'-fluoro-3' - Imino-spiro[cyclopropane-1,-isoporphyrin]_2'-yl)ethanone hydrobromide salt 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane_丨, 3' _isoporphyrin]-oxime-imine 41g (156mg, 0. 59mmol) and 1-[3-(1-adamantyl)-4-methoxy-5-morpholinylphenyl]- 2-Bromo-ethanone I7h (298 mg, 0.67 mmol) was dissolved in 5 mL of tetrahydrofuran, and triethylamine (m.m. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product [3-U-adamantane]-4-decyloxy-5-morpholinylphenyl]_2-(5 ,,6,-diethyl 95255 194 201242964 oxy-4'-fluoro-3'-imino-spiro[cyclopropane__丨, hydrazine, _isoindolyl) ethyl ketone hydrobromide 47 ( 126 mg, white powder), yield 2', MS m/z (ESI): 632 [M+l] · 29.9%. 4 NMR (400 MHz, DMS0-forming, ppm): δ 9 74 (heart 9.16 (set factory s, 1H), 7.57 (m, 2H), 7 〇 7 (s, 1 Η) Γ · S' 1H) ' 2H), 4. 25 (q, 7.2 Hz, 2H), 4. 12 (q, y, 5.44 (S, 2H), 3.96 (s, 3H), 3.81 (m, 4H), 3. 02 (m,4H) such as '(m,9H),1.76 0η,6H),1.72〇n,2H)' l.66(m 2,2.06 (t,7.2 Hz,3H),1.31 (t,/= 7·2 Hz, '3h), i.40 Example 48 卜 [3-[(l: 5 幻~ 3- azabicyclo[3. l· 〇] _3_ yl]~5' 1-4 Methoxyphenyl], 2-(5,6, _diethoxy-4, _fluoro_3, butyl snail [cyclopropan-1,1,-iso-f-lin], 2,- Base) ethyl ketone gas (four) ^ base ~

First step cyclopropane-1, diethyl dicarboxylate 95255 195 201242964 Under ice bath, 60% sodium hydride (22.0 g, 0.51 mol) was dissolved in 150 mL of toluene, and 2-acrylic acid was added dropwise. A mixed solution of 48a (50.0 g, 0.5 mol) and ethyl 2-chloroacetate 48b (61. 3 g, 0.5 mol) was stirred for 12 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by distillation in vacuo to yield fractions from 65 to 92 ° C to give the title product bis-propanone-1,2-di-t-acid diethyl ester 48c (39.78 g, colorless liquid). Rate: 42.8%. _ MS m/z (ESI): 187 [M+l] The second step [(15; 2N)-2-(hydroxyindenyl)cyclopropyl]methanol, lithium aluminum hydride (8. 98) g,0. 24mol) was dissolved in 180mL of tetrahydrofuran, hydrogen was replaced three times, and 20mL of tetrahydrofuran solution of cyclopropane-1,2-dicarboxylate 48c (22.0 g, 0.12 mol) was added dropwise. The reaction was stirred at 70 ° C for 3 hours, and the reaction was further stirred at room temperature for 12 hours. 22 mL of saturated ammonium hydride solution was added dropwise to the reaction solution under ice-cooling, concentrated under reduced pressure, ethyl acetate (200 mL) was added, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent system B. The title product [(15; 250-2-(hydroxyindenyl)cyclopropyl] decyl alcohol 48d (1.44 g, yellow liquid) was obtained, yield: 9. 4% and [(15; 2 -(Hydroxymethyl)cyclopropyl]methanol 48e (5.3 g, yellow liquid), yield: 43.9%. 4 Li 1^(4〇〇 elbow 1^, 〇〇 (:13,0?111):5 3.81 (111, 21 〇, 3.53 (set s, 2H), 3.10 (m, 2H), 1.03 (m, 2H), 0.45 (m, 2H) 196 95255 201242964 】H NMR (400MHz, CDCls, ppm): δ 4. 11 (m, 2H), 3. 24 (m 4H), 1.32 (m, 2H), 0.81 (m, 1H), 0.22 (m, 1H) ' The third step (1 especially 25)-1, 2-二(乙曱 曱 环 环 院 院 冰 冰 冰 将 三 三 28 28 28 28 28 28 28 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 7mol), add 30mL [(15·, 2A〇-2-(pyridinyl)cyclopropyl] decyl alcohol 48e (5. 22g, 0. 0 51 mo 1) of B guess solution at room temperature The reaction was dropped for 12 hours. The title product (1 especially 251) -1,2--(&gt) was obtained by adding ethyl acetate (ethyl acetate), filtered, and the filtrate was concentrated under reduced pressure. ; 曱 曱 ) 环 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 48 ), 1. 18 (m, 1H), 0.43 (m, 1H) The fourth step ^ l-[3-[(l疋551)-3-azabicyclo[3. 1. 0]hex-3-yl) ]-5-tert-Butyloxyphenyl]ethanone 1-(3-Amino-5-tert-butyl-4-methoxyphenyl)-ethanone 8b (1. 0 g, 4. 5 mmol And (1疋25)-1,2-di(bromomethyl)cyclopropane 48f (2.66 g, 9.0 mmol) dissolved in 20 mL of water, added potassium carbonate (680 mg, 4.95 mmol) '120 ° C microwave stirring After the reaction was carried out for 20 minutes, 20 mL of ethyl acetate was added, and the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phase was washed with water (50 mL) and saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc </ </RTI> [(1疋5 幻_3-azabicyclo[3·1.0]hex-3-yl]+tert-butyl-4-yloxy phenyl ketone 48g (596mg, yellow liquid), yield: 45. 9%. MS m/z (ESI): 288 [M+l] H NMR (400 MHz, CDCh, ppm): δ 7.52 (d, / = 2. 0 Hz, 1H), 7.37 (d, /= 2.0 Hz, 1H ), 3.64 (s, 3H), 3. 61 (m, 2H), 3.00 (m, 2H), 2.56 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H), 0.6 (m, 2H) Step 5 1-[3-[(1 especially 55^-3-azabicyclo[3. i. 〇]hexyl-3-yl]_5_tert-butyl-4-methoxyphenyl]- 2-Bromo-ethanone at 40 ° C 'will [3-[(1疋5Λ-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methyl 48g (2.0 g, 6.97 mmol) of oxyphenyl]ethanone was dissolved in 20 mL of air-formed 'bronium bromide (3. Ug, 13.94 mmoi), and the reaction was stirred for 12 hours. The residue obtained was purified by eluent from EtOAc (EtOAc) eluting 5-[tert-Butyl-4-decyloxyphenyl]-2-oxa-ethanone 48h (558 mg, yellow solid), yield: 21.9% MS m/z (ESI): 368 [M+ l] 11A NMR (400 MHz, CDCh, ppm): δ 7.55 (d, / = 2. 〇Hz, 1H), 7.43 (d, /= 2.0 Hz, 1H), 4.42 (s, 2H), 3.64 (s , 3H), 3.60 (m, 2H), 3.01 (m, 2H), 1.56 (m, 2H), 1.41 (s, 9H), 0.6 (m, 2 H) Step 6 198 95255 201242964 1-[3-[(1 and,551)-3-Azabicyclo[3. 1. 〇]hexyl-3-yl]_5_tert-butyl-4-methoxy Phenyl]-2-(5',6'-diethoxy-4,-fluoro-3,-imino-spiro[cyclopropan-1,1 '-iso-β丨β朵琳]- 2'-yl) ethyl ketone hydrogen oxalate salt 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane_ι,3,-isoindolin]-indole-imine 41g ( 161 mg, 0.71 mmol) and 1-[3-[(1 550-3-oxabicyclo[3.1.0]hex-3-yl]-tert-butyl-4-decyloxyphenyl]-2 The solution was dissolved in 5 mL of tetrahydrofuran, and triethylamine (0.1 mL, 0. 72 mmol), 25 was added. (: The reaction was stirred for 12 hours. </ RTI> </ RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTI ID=0.0></RTI> <RTIgt; 3· 1. 0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-(5,6'-diethoxy-4, ~fluoro-3' - Imino-spiro[cyclopropane-1, fluorenyl-isoporphyrin]-2'-yl)ethanone hydroperate 48 (118 mg, white powder), yield: 30·7% MS m/z (ESI): 550 [M+1] H NMR (400 MHz, DMSO-i/6, ppm): δ 9·34 (Z?r. s, iH), φ 9.05 {br. s, 1H), 7.49 (d, /= 1.6 Hz, 1H), 7.39 /= 1.6 Hz, 1H), 7.04 (s, 1H), 5.22 (s, 2H), 4.24 (Q} / = 7. 2 Hz, 2H), 4.12 ( q, / = 7. 2 Hz, 2H), 3.61 (s&gt; 3H), 3.54 (d, /= 8.8 Hz, 2H), 2.99 (d, / = 8. 8 Hz, 2H), 1.80 {br. s , 2H), 1.66 (m, 4H), 1.40 (t, / = 7. 2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, / = 7. 2 Hz, 3H), 〇, 6l ( m, 1H), 0.55 (m, 1H) Example 49 2-[8-tert-butyl-6-[2-(5',6'-diethoxy- 4'-fluoro-3'-imine基__ 199 95255 201242964 snail [cyclopropan-i,r-iso- ten-lin]- 2,_yl) ethyl aryl]_2,3_diaza-1,4- stupid and evil 4-yl] acetonitrile hydrobromide

First step 2-[8-tert-butyl-6-[2-(5',6,diethoxy_4,monofluoro-3, _imino]-spiro[cyclopropane-1,1'- Isoporphyrin]-2'-yl)ethinyl]_2,3-dihydro-1,4-benzox-4-yl]acetonitrile hydrobromide 5',6'-diethoxy Base-7'-fluoro-spiro[cyclopropane_丨,3' _isoindole]-1 -imine 41g (160mg, 0'61mmol) and 2-[6-(2-bromo-ethenyl) -8-tert-Butyl-2,3-dihydro-1,4-benzoxazine-4-yl]acetonitrile i6b (320 mg, 0.91 mmol) was dissolved in 5 mL of tetrahydrofuran, and triethylamine (〇. 0.72 mmol) 'The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (10 mL×3) and dried in vacuo to give the title product 2-[8-t-butyl-6-[2-(5',6'-diethoxy~4 '---3, -imino-spiro[cyclopropan-1, Γ-iso-indolyl]-2,-yl)ethinyl]-2,3-dihydro-1,4-benzo Oxazin-4-yl]acetonitrile hydrobromide 49 (150 mg, yellow powder), yield: 40.2%. MS m/z (ESI): 535 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 9.40 (Z?r. s, 2H), 200 95255 201242964 7. 67 (s , 1H), 7.41 (s, 1H), 7. 05 (s, 1H), 5.41 (s, 2H) 4.85 (s, 2H), 4.39 (m, 2H), 4.24 (q, /= 7.2 Hz, 2H ), 4. 11 (q, / - 7. 2 Hz, 2H), 3. 36 (m, 2H), 1. 85 (m, 2H) 1.65 (m, 2H), 1.39 (t, /=7. 2 Hz, 3H), 1.35 (s, 9H), 1.30 (t, / = .7. 2 Hz, 3H) Example 50 1-(8-tert-butyl-4-mercapto-2,3-dihydrogen -1,4-benzoxazine-6-yl)_2_(5,6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan __ι,1,_ Iso-φ porphyrin]-2'-yl)ethanone hydrobromide

First step 1-(8-tert-butyl-4-mercapto-2,3-dihydro-1,4-benzoxazine-6-yl)-2-(5,6-diethoxy-4 -Fluoro-3'-imino-spiro[cyclopropylhu-1, Γ_isoporphyrin]~2' yl) ethyl ketone hydrobromide 5',6'-diethoxy-7 '~Fluoro-spiro[cyclopropane-oxime, 3, _isoporphyrin]-1' _imine 41g (157mg, 0. 59mmol) and 2-bromo-1-(8-tert-butyl-4-anthracene Base-2,3-dihydro-1,4-benzoxazine-6-yl)ethanone 19b (23 mg, 0.71 mmol) was dissolved in 5 mL of tetrahydrofuran and triethylamine (1 mL, 0.72 mmol) The reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (10 mL) and water (1 mL mL) and dried in vacuo to give the title product i-(8- 95255 201 201242964 tert-butyl fluorenyl-2, 3-dihydro-1,4- Benzopyrene. Qin~~6-yl)-2_(5',6'-diethoxy-4'-fail-3' _imino-spiro[cyclopropyl _u, _ 0份1#]-2'-yl) Ethyl ketone A oxalate 50 (164 mg, pale yellow powder), Yield: 46.7%. MS m/z (ESI): 510 [M+l] 'H NMR (400 MHz, DMSO-i/e, ppm): δ 9.34 (^r S) m), 9. 07 {br. s, 1H) , 7. 30 (s, 1H), 7. 22 (s, m), 7. 04 (s, 1H), 5.21 (s, 2H), 4.35 (in, 2H), 4.24 (q, / = 7. 2 Hz, 2H), 4. 13 (q, / = 7. 2 Hz, 2H), 3. 34 (m, 2H), 2. 94 (s, 3H), 1.78 (m, 2H), 1.67 (in , 2H), 1.41 (t /= 7 2 Hz, 3H), 1.36 (s, 9H), 1.31 (t, / = 7.2 Hz, 3H) Example 51 1-(8-tert-butyl-4-ethyl -2,3-dihydro-1,4-stupid and agonistic _6_yl)_2_ (5,6 _-ethoxy-4-gas-3-imino-spiro [cyclopropyl]_1 1 '一异°弓10朵琳】-2'-based) B-hydrogen;

The first step is 1-(8-tert-butyl-4-ethyl-2,3-dihydro-1,4- benzoxanthroline-6-yl)_2_ (5,6 _-ethoxy 4) _鼠_3 _imino-- snail [cyclopropanone _ 1 1, _ iso 0 引 ° 朵 淋] - 2 '-yl) ethyl ketone hydroperate 95255 202 201242964 will 5 ', 6 ' - two Ethoxy-7'-fluoro-spiro [cyclopropyl-i, 3'-iso, n-linin]-1'-imine 41g (165mg, 0.62mmol) and 2-di-1-(8- tert-Butyl-4-ethyl-2,3-dihydro-1,4-benzo-oxazin-6-yl)-ethanone (255 mg, 0.75 mmol) was dissolved in 4 mL of tetrahydrogen Triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred at 25 ° C for 12 hours. Filtration, filtration, cake with Zhengxuan (10 mL) and water-washed (10 mL×3), dried in vacuo to give the title product 1-(8-tert-butyl-4-ethyl-2, 3-dihydro-1,4- Benzopyridin-6-yl)-2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane#-Μ'-isoporphyrin] -2'-yl)ethanone hydrobromide 51 (133 mg, white powder), yield: 35.2%. MS m/z (ESI): 524 [M+l] NMR (400 MHz, DMSO-' ppm): δ 9.35 (Δ/·. s, iH) 9.04〇r. s,1H), 7.24 (s,1H) ), 7.22 (s, 1H), 7.04 (s, 1H), 5. 19 (s, 2H), 4. 29 (t, / = 4. 4 Hz, 2H), 4. 24 (q /= 7. 2 Hz, 2H), 4.12 (q, / = 7. 2 Hz, 2H), 3.43 (q, /= 7. 2 Hz, 2H), 3.37 (t, / = 4. 4 Hz, 2H), 1.78 ( m, 2H), 1.66 (m, 2H), 1.40 (t, /= 7.2 Hz, 3H), 1.36 (s, 9H), 1.31 (t, /= 7.2 Hz, 3H),1·12 (t, / = 7.2 Hz 3H) ? Example 52 l-[3-tert-Butyl-4-decyloxy-5-(1-piperidinyl)phenyl]_2-(7-imino-2, 5-di Mercapto-5-phenyl-pyrrolo[3,4-6]pyridine-6-yl)ethane-gas bromide 95255 203 201242964

The first step is [3-tert-butyl-4-fluorenyl-5-(1-branches)phenyl]_2-(7-imino-2,5-dimethyl-5-phenyl- Pyrrolo[3,4_arsenyl-6-yl)ethanone hydrobromide salt 2,5-mercapto-5-phenyl-pyrene[3,4-do] than bite-7- Amine 9f (237 mg, 1 mmol) and 2-bromo-i-[3-tert-butyl-4-methoxy-5-(1-piperidyl)phenyl]-ethanone 12b (441.6 mg, 1.2 mmol) The solution was dissolved in 3 mL of N,N-dimethylformamide and stirred for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL mL), and the organic phase was combined and washed with saturated sodium carbonate solution (10 mL &lt;&lt;&gt;&gt;&lt;3&gt;), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product 1-[3-tert-butyl-4-decyloxy-5-(p-butyl)phenyl]-2- (7-Imino-2,5-dimethyl-5-phenyl ratio d-[3,4-)pyridin-6-yl)ethanone hydrobromide 52 (150 mg, pale yellow solid) , yield: 24.8%. MS m/z (ESI): 525 [M+l] 4 NMR (400 MHz, DMSO-ppm): δ 7. 92 (d, /= 7. 6 Hz, 204 95255 201242964 1H), 7.63 (d, /= 7.6 Hz, 1H), 7.46 (m, 7H), 5.43 (d, ·/= 18.8 Hz, 1H), 5. 03 (d, /= 18. 8 Hz, ih), 3.94 (s, 3H) , 2.92 (m, 4H), 2.67 (s, 3H), 1.99 (s, 3H), 1.71 (m, 4H), 1.54 (m, 2H), 1.33 (s, 9H) Example 53 2-(5, ,6,-diethoxy- 4'-fluoro_3' _imino-spiro[cyclopropane-1, hydrazine-isoporphyrin]-2,-yl)-bu (4-methoxy- 3-morpholinyl~5-trimethyldecyl-phenyl)ethanone argonate

Step 1 1-(4-Phenyl-3-moth-phenyl)ethylidene 1-(4-Hydroxyphenyl)ethanone 53a (4.0 g, 29.38 mmol) was dissolved in 250 mL of concentrated aqueous ammonia. Aqueous solution of iodine (7·46 g, 29·38 mmol) and potassium iodide (23.75 8, 143.8181111〇1), 50° (: stirring reaction for 48 hours. Filtration, filtrate adjusted with concentrated hydrochloric acid 100 mL pH = 1 'filter' filter cake with water Washing (100 mL x 3) <RTI ID=0.0></RTI> <RTI ID=0.0></RTI></RTI> <RTI ID=0.0></RTI> z (ESI): 261 [Ml] 丽 R (400 MHz, DMS0-忒, ppm): δ 11. 13 (s, 1H), 8. 10 (d, /= 2.0 Hz, 1H), 7.70 (dd, J, = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.81 (d, /= 8.4 Hz, 2H), 2.34 (s, 3H) The second step l-(3_破_4_曱基基基) E-hole was dissolved in 50 mL of acetone by adding 1_(4-carbyl-3-bromo-styl)acetamidine 53b (3.52 g, 13 minol), and methyl benzene-4-carboxylate (2 mL, 14 mmol) and potassium carbonate were added. (2.78g, 20 liters ol), stirred at 50 ° C for 6 hours. Filtration, the filtrate was concentrated under reduced pressure, and purified by eluent column chromatography using eluent system B The residue was obtained as the title product: 1-(3-iodo-4-methoxyphenyl)ethanone 53c (3. 03 g, m. 277 [M+l] NMR (400 MHz, CDC13, ppm): δ 8.39 (d, /= 2.4 Hz, 1H), 7.95 (dd, /; = 8. 4 Hz, 2. 4 Hz, 1H), 6.85 (d, /= 8.4 Hz, 1H), 3.96 (s, 3H), 2.55 (s, 3H) The third step 1-(4-decyloxy-3-morpholinephenyl)ethanone 1_(3_ Moth _4-mercaptophenyl) acetam 53c (3. 03g, 10. 96ππηο1) and 2-dicyclohexylphosphino-2'-(Ν, Ν-dimethylamine)-biphenyl (216mg, 0 55mmol) dissolved in 120mL of benzene, added palladium / carbon (302mg, 10%), sodium tert-butoxide (2. 10g, 21.91mmol) and morphine (1.9mL, 21.91mmol), 80 °C disturbance 206 95255 201242964 Mix reaction for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj Oil)) Yield: 68.8%. MS m/z (ESI): 236 [M+l].H NMR (400 MHz, CDCh, ppra): δ 7.66 (dd, = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.58 (d, / = 2 4 Hz, 1H), 6.89 (d, /= 8. 4 Hz, 1H), 3.94 (s, 3H), 3.90 (m, 4H), 3. 10 (m, • 4H), 2.56 (s, 3H The fourth step 4-[5-(M-dimethoxyethyl)-2- methoxyphenyl]morpholine 1-(4-decyloxy-3-morphinylphenyl)ethanone 53d (971 mg, 4.13 mmol) and tridecyl orthoformate (1.4 mL, 12.38 mol) dissolved in 40 mL of methanol 'Add D(+)-l〇-camphoric acid (l.〇54g, 4.54mmol) , disturbed reaction for 12 hours. Add 626 mg of potassium citrate to the reaction mixture, stir the mixture for 5 hours, add 50 mL of water, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated sodium carbonate solution (50 mL×2), anhydrous sodium sulfate Drying, filtration, and concentrating the filtrate under reduced pressure to give the title product 4-[5-(1,1-dimethoxyethyl)-2- methoxy phenyl]. The yield: 94.0%. MS m/z (ESI): 282 [M+l] 'H NMR (400 MHz, CDCh, ppm): δ 7.13 (dd, //= 8.8 Hz, J2 = 2.0 Hz, 1H), 7.06 (d, / = 2. 0 Hz, 1H), 6.84 (d, / = 8. 8 Hz, 1H), 3. 90 (m, 4H), 3. 87 (s, 3H), 3.. 18 (s 207 95255 201242964 6H), 3.09 (m, 4H), 1.53 (s, 3H) The fifth step [5-(1,1-dimethoxyethyl)-2-nonyloxy-3-morphinyl]] Dissolving 4-[5-(1,1-dimethoxyethyl)-2-nonyloxyphenyl]morphine 53e (1.09 g, 3.88 mmol) in a dry ice-acetone bath Tetramethylethylenediamine (116 yL, 0 78 mm 〇1) and n-butyllithium (3.1 mL, 7.76 mmol) were added to 40 mL of n-hexane. The reaction was stirred at room temperature for 4 hours, and trimethyl group was added under ice bath. Chlorohydrazine (975 /z L, 7.76 mm 〇l) was stirred at room temperature for 12 hours. 50 mL of a saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3), and the organic phase was combined, washed with water (2 〇mL×2) and saturated sodium chloride solution (20 mL×2) The title product [5-(1,1-dimethoxyethyl)- 2-decyloxy_3_morpholinylphenyl]-tridecyldecane 53f (1. 31 g, m. 7%). Yield: 95.7%. MS m/z (ESI): 354 [M+l].H NMR (400 MHz, CDCh, ppm): δ 7.14 (d, / = 2. 0 Hz, 1H), 7.09 (d, /= 2.0 Hz, 1H), 3.90 (s, 3H), 3.87 (m, 4H), 3.19 (s, 6H), 3.10 (m, 4H), 1.53 (s, 3H), 0.28 (s, 9H) 1-(4-methoxy-3-morpholinyl-5-tridecylfluorenyl-phenyl)ethanone [5-(1,1--methoxyethyl)-2-methoxy Benzyl-3-phenanthylphenyl]_tridecyldecane 53f (1.31 g, 3.71 mmol) was dissolved in 2 acetic acid, 95255 208 201242964 was added to the second desert salt (1. 19 g, 3.71 mm 〇l), the reaction was stirred for 2 hours. Add 30 mL of saturated sodium carbonate solution to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phase, wash with saturated sodium bicarbonate solution (2〇mLx2) and saturated sodium chloride solution (20mLx2), anhydrous sulfuric acid The sodium was dried, dried over hydrazine, and concentrated under reduced pressure. The residue obtained was purified from the eluent system B by the sulphur column chromatography to give the title product 2-bromo-1-(4-methoxy-3-? 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. φ MS m/z (ESI): 386 [M+l] ΐ NMR (400 MHz, CDCI3, ppm): δ 7.70 (d,, = 2.4 Hz, 1H), 7.63 (d, /= 2. 4 Hz, 1H), 4.42 (s, 2H), 3. 97 (s, 3H), 3.90 (m, 4H), 3.11 (m, 4H), 0.32 (s, 9H) Step 7 2-(5', 6' -diethoxy-4'-gas-3'-imino-spiro[cyclopropanone i, _iso-sigma-dolin]-2'-yl)-1-(4-decyloxy-3 -Mallinyl-5-trimethyl sulphate-phenyl)ethanone oxime bromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3' - different. π 系 ]]-Γ-imine 41g (156mg, 0·59mmol) and 2-bromo-1-(4-decyloxy-3-? Ethyl ketone 53 g (298 mg, 〇.) was dissolved in 5 mL of tetrahydrofuran, triethylamine (〇.lmL, EtOAc) was added, and the reaction was stirred at 25 ° C for 12 hours. Filtration, the filter cake was washed with n-hexane (1 mL) and water (10 mL×3) and dried in vacuo to give the title product 2-(5',6,-diethoxy-4'-fluoro-3'-imido. - spiro [cyclopropane-1, hydrazine-isoporphyrin]-2,-yl)-1-(4-methoxy-3-morphinyl-5-trimethyl sulphate-phenyl) Hydrogen 95255 209 201242964 Bromate 53 (126 mg, yellow powder), yield: 29 9%. MS m/z (ESI): 632 [M+l] 4 NMR (400 MHz, DMSO-' ppm): δ 9 46 (&amp;. s, 2H), 7.67 (d, /= 2. 4 Hz, 2H ), 7. 〇7 (s, 1H), 5. 49 (Sj 2^^ 4.24 (q, /= 7.2 Hz, 2H), 4.11 (q&gt; /=7 2 Hz, 2H), 3.91 (s' 3H ) 3. 3.79 (m, 4H)' 3.05 (m, 4fj), 179 (m, 2H), 1.66 (m, 2H), 1.39 (t, ·/= 7.2 Hz, 3H), 1.30 (t, / = 7.2 Hz, 3H), 0.29 (s, 9H) Example 54 l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]_2_(5,,6, _ Ethoxy-4'-fluoro-3'-imino-spiro[cyclopropane_丨,丨' _isophthalene]-2'-yl)ethanone hydrobromide

The first step is [3-tert-butyl-4-decyloxy-5-(1'-piperidinyl)phenyl]_2-(5,6,1-diethoxy-4'-fluoro-3 '-Imino-spiro[cyclopropane-1,1,-isoindolyl]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7'-fluoro- Spirulina [cyclopropane-1,3'-isoindoline]-1'-imine 41g (198mg, 0.75mmol) and 2-bromo-l-[3-tert-butyl 95255 210 201242964-4-methoxy Base-5-(1-p-pyridinyl)phenyl]ethanone 12b (324 mg, 〇.88mm〇1) was dissolved in 5 mL of tetrahydrofuran, and added triethylamine (〇15 mL, L 〇8 mm〇1), 25 C The reaction was disturbed for 12 hours. Filtration of the 'filter cake with n-hexane (1 mL) and water (10 mL×3) and dried in vacuo to give the title product </ </ </ </ </ </ </ ]-2_(5,6, _diethoxy_4,-fluoro_3, _imino-spiro[cyclopropan-1, Γ-iso-bendolin]_2,-yl)ethanone 2%。 Hydrobromide 54 (257 mg, white powder), yield: 54.2%. MS m/z (ESI): 552 [M+l] 匪 R (400 MHz, DMS0-i/6, ppm): δ 9. 36 (/?厂s, 1H), 9·08 {br. s , 1H), 7.59 (s, 1H), 7. 54 (s, 1H), 7. 05 (s, 1H), 5.24 (s, 2H), 4.24 (q, / = 7. 2 Hz, 2H), 4. 12 (q, J = 7. 2 Hz, 2H), 3.96(s, 3H), 2. 97 (ra, 4H), 1.82 (m, 2H), 1.73 (m, 4H), 1.66 (m, 2H), 1.55 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.38 (s, 9H), 1.31 (t, J = 1.2 Hz, 3H) Example 55 φ 1_[3—[( 1 especially 5 «-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-decyloxyphenyl]-2-(5,6-diethoxy-4 -Fluoro- 3 -imino group j, bis-indenyl-isoindoline ~ 2-yl) ethyl ketone hydrobromide

211 95255 201242964 First step 1_[3-[(1 brother 55|)-3-heterobicyclo[3.1.0]hex-3-yl]-5-succinyl-4-decyloxy]]- 2-(5,6-diethoxy-4-fluoro-3~imino-1,1-dimethyl-iso-sigma-indolyl-2-yl)ethyl ketone argonate will be 5, 6-diethoxy-7-fluoro-3,3-dimercapto-isoindole_; [-amine 24d (258 mg, 〇·97 mmol) was dissolved in 4 mL of N,N-dimercaptocarbamide. Add 1-[3-[(1 friend, 55〇-3-Il heterobicyclo[3·1]]-3-yl]-5-tert-butyl-4-methoxyphenyl]-2- Bromo-ethanone 48h (558mg, i. 〇 7mmol), stirred for 12 hours. Add i〇mL water and 1〇mL acetic acid acetate to the reaction mixture, combine the organic phase, water (5mLx3) and saturated sodium chloride solution The residue (1 mL) was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 3-Azabicyclo[3.1.〇]hexyl-3-yl]_5-tert-butyl-4-methoxyphenyl]-2-(5,6-diethoxy~~4-fluoro-3 -Imino-1,b-dimethyl-isoindolin-2-yl)ethanone hydrobromide 55 (36 mg, yellow solid), yield: 5. 9% MS m/z (ESI): 552 [M+1] NMR (400 MHz, MSO-A, ppm): δ 9.34 s iH) 8.97 (^r. s, 1H), 7.53 (s, 1H) , 7.48 (s, 1H), 7. 44 (s! 1H), 5.44 (s, 2H), 4.26 (in, 2H), 4. 11 (m, 2H), 3 61 (s, 3H), 3.55 ( In, 2H), 2.99 (m, 2H), 1.63 (m, 2H) 1 50 (s, 6H), 1.41 (t, /= 7. 2 Hz, 3H), 1.39 (s,1 31 (t, / = 7.2 Hz, 3H), 0.60 (m, 2H) Example 56 95255 212 201242964 1-[3-[(1 especially 5^-3-azabicyclo[3·i. 〇] 勺-基]_5_ Tert-butyl 4-methoxyphenyl]-2-(5',6,diethoxy-3,imine-based snail [cycloheximide-1,1-isoindole]] , _ base) ethyl ketone hydrobromide

The first step 1-[3-[(1 especially 5«-3-azabicyclo[3·丨.0]hex-3-yl]_5_tert-butyl-4-methoxyphenyl]-2- (5',6'-diethoxy-3,-imino-spiro[cyclopropane-1, hydrazine-isoindoline]-2'-yl)ethanone hydrobromide 5',6 '-Diethoxyspiro[cyclopropane_i,3, _isoporphyrin]&lt;,_imine hydrobromide 7d (172mg, 0·70mmol) was dissolved in 4mL of tetrahydrofuran φ, added to Bu [3 1-[(1疋55)-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-decyloxy]-2-,; odor-acetone 48h (360mg, 0.98mmol) and triethylamine (0. lmL, 0.72 liter ol), stirring reaction for 12 hours. Filtration, filter cake washed with n-hexane (l〇mLx2) and water (10mLx3), vacuum drying 'To get the title product 1-[3-[(1 especially 550-3-azabicyclo[3.1.0]hex-3-yl]-5-tert-butyl-4-methoxyphenyl]-2-( 5,6,-Diethoxy-3'-imino-spiro[cyclopropane-1,1,-isoindoline]-2'-yl)ethanone hydrobromide 56 (27 mg, white Powder), Yield: 6.3% MS m/z (ESI): 532 [M+l] 213 95255 201242964 4 R (400 MHz, DMSO-A, ppm): δ9·64 (Ζ?/·· s,1H),9.08 (br. s, 1 H), 7.87 (s, 1H), 7. 50(s, 1H), 7.40 (s, 1H), 7. 05(s, 1H), 5. 18(s, 2H), 4. 17(q, /=7. 2 Hz, 2H), 4.11 (q, /=7. 2 Hz, 2H), 3.61(s, 3H), 3. 55(d, /=8. 8 Hz, 2H), 2. 99 (d, /=8. 8 Hz, 2H), 1.72 (m, 2H), 1.63 (m, 4H), 1.38 (m, 15H), 0. 62 (d, /=4. 4 Hz, 1H), 0. 55(d, /=4. 4 Hz, 1H) Example 57 2-(5,6-Diethoxy-4-gas-3-imino-1,1-diindenyl-isoindole 〇 〇 -2- -2--2-yl)-1-(4-decyloxy-3-morpholinyl-5-trimethylhydrazine-phenyl)ethanone hydrobromide

The first step is 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)-1-(4-oxime Benzyl-3-morpholinyl-5-trimethylhydrazine-phenyl)ethanone hydrobromide

5,6-Diethoxy-7-fluoro-3,3-dimercapto-isoindole-p-amine 24d (266mg, l.〇mm〇i) and 2-bromo-b (4-methoxy 53 g (425 mg, 1.1 mmol) of benzyl-3-morpholine-5-trimethylsulfanyl-phenyl)ethanone was dissolved in 5 mL of N,N-didecylcarbamide, and the reaction was stirred for 12 hours. 5 mL of 214 95255 201242964 water's aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate Filtration of the 'filter cake with n-hexane (1 mL) and water (10 mL) and dried in vacuo to give the title product 2-(5,6-diethoxy-4-fluoro-3-imino-M- Mercapto-isoindoline-2-yl)-1-(4-decyloxy-3-morpholinyl-5-trimethylsulfonium-phenyl)ethanone hydrobromide 57 (84 mg, yellow powder , yield: 12. 0%. MS m/z (ESI): 572 [M+l] # 1H 丽 R (400 MHz, DMS0-d6, ppm): δ 9.35 (red.s, 1H), 8.99 (br. s, 1H), 7. 67(m, 2H), 7.46(s, 1H), 5.47(s, 2H), 4. 26(q, /=7. 2 Hz, 2H), 4. 10(q, /=7.2 Hz, 2H), 3.93 (s, 3H), 3.89 (m, 4H), 3. 05(m, 4H), 1.51 (s, 6H), 1.41 (t, /=7.2 Hz, 3H), 1.31(t, / =7.2 Hz, 3H), 〇.31(s, 9H) Example 58 1-(3-tert-butyl-4-methoxy-5-pyrrolidin-1-yl-phenyl)-2-(7 -imino-2-methoxy-5-mercapto-5-phenyl-σ ratio slightly [3, 4-do] σ ratio bit-6-yl) ethyl ketone hydrobromide

215 95255 201242964 First step 1-(6-methoxy-3-pyridine)-i-phenylethanol dry ice-acetone bath, 5-bromo-2-yloxy-pyridine 58a (21. 〇g, lllmmol Dissolved in uOmL diethyl ether, a solution of 2. (10) n-butyllithium (49 μL, 123 mmol) in n-hexane was added dropwise, and the mixture was stirred for one hour, and then acetophenone (14.4 mL, 123 ramol) was added. Add 50 mL of the mixture and gasification recording solution to the reaction mixture. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with saturated sodium carbonate solution (2 mL mL), dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) %. MS m/z (ESI): 230 [M+l].H NMR (400 MHz, CDCh, ppm): δ 8. 26 (s, 1H), 7. 63 (m, 6H), 6.72 (m, 1H) ), 3.96 (s, 3H), 1.99 (s, 3H) The second step is 5-(1-azido-1-indolyl-ethyl)_2-methoxyacridine in an ice bath, 1-(6) -decyloxy-3·&quot;pyridine)-1-phenyl-ethanol 58b (14.4 g, 63 mmol) and sodium azide (I2.3 g, 189 mmol) dissolved in 72 mL of water 'drop 56raL concentrated hydrochloric acid, stir the reaction 12 hours. To the reaction mixture, 800 mL of a saturated sodium hydrogencarbonate solution was added to adjust the pH to 7 to 8 and extracted with ethyl acetate (200 mL×3). The organic phase was combined, washed with saturated sodium sulfate solution (50 mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The title product was 5-(1-azido-1-phenyl~ethyl)-2-methoxypyridine. The crude product was 58c (16.0 g, yellow oil). </ RTI> </ RTI> <RTIgt; = 9. 2 Hz, 1H), 3.98 (s, 3H), 2.05 (s, 3H) Step 3 5-(1-azido-1-phenyl-ethyl)-2-methoxypyridinyl 1 ~Oxide 5-(1-azido-1-phenyl-ethyl)-2-decyloxy-acridine 58c (16.0 g, 63 mmol) was dissolved in 200 mL of dichloromethane, added to the gas Oxybenzoic acid (21. 7 g, 126 mmol) was scrambled for 13 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was dried over anhydrous sodium sulfate (MgSO4) The methoxy group is a bit of 1-oxide 58d (12.0 g, light yellow oil), yield: 70. 6 〇 / 〇. • MS m/z (ESI): 271 [M+l] Step 4 3-(1-Azide-U-phenyl-ethyl)- 6-decyloxy-0-bite-2-nitrile 5--( 1-Lead gas-1-phenyl-ethyl)_2_methoxy-η is dissolved in l20 mL of acetonitrile and cyanotrimethylnonane (17). · 6 mL, 132 mmol) and dimethylaminophosphonium chloride (3.63 mL, 39.5 匪〇1) 'Stirring reaction for 24 hours. To the reaction mixture, 1 〇〇 mL of digastric broth 'combined organic phase' was washed with saturated sodium bicarbonate solution (2 〇 mL×3) and saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, and passed over 95 255 217 201242964 滤 'Filter, liquid and concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent column chromatography to give the title product 3-(1-azido-1-phenyl-ethyl)- 6-indole. Oxy-pyridine-2-carbonitrile 58e (4.5 g, pale yellow oil), yield: 48.9%. MS m/z (ESI): 280 [M+l] Step 5 2Methoxy-5-fluorenyl-5-phenylpyrazine [3, 4-do] 〇比〇定-7-imine 3-(1-azido-1-phenyl-ethyl)_6-fluorenyloxy-0 ratio biting 2-nitrile

58e (4.4 g, 15, 7 mmol) was dissolved in 120 mL of tetrahydrofuran, and 6 mL of water and triphenylphosphine (8.26 mg, 31.5 mmol) were added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford the title product 2-decyloxy-5-fluorenyl-5-phenyl-6)7-° [3,4] pyridine-7-imine 58f (3.0 g, white solid), yield: 75.2%. MS m/z (ESI): 254 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 7.95 (d, / = 8. 4 Hz, 1H), 7.48 (m, 2H) ), 7.28 (m, 2H), 7.20 (m, ih), 6.84 (d, / = 8.4 Hz, 1H), 3.95 (s, 3H), 1.71 (s&gt; 3H) Step 6 1-(3-Uncle Butyl-4-methoxy-5-pyrrolidine-l-yl-styl)_2_(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3, 4-[]pyridin-6-yl) ethyl ketone hydrobromide 2-methoxy-5-mercapto-5-phenyl-6 and -pyrrolo[3,4-Z?]pyria ~7 -imine 58f (253 nig, lminol) and odor-1 -(3~tert-butyl-oxime 95255 218 201242964 bis-5-pyrrolidine-fluorenyl-phenyl)ethanone 8d (424 8 mg, 12 mm 〇1 Dissolved in 5 mL of methanol, added triethylamine (〇 166 mL, 12 〇1), and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -phenyl)-2-(7-imino-2-methoxy-5-indolyl-5-phenyl-indolo[3,4-6]pyridin-6-yl)ethanone Hydrogen oxalate 58 (6511^, pale yellow solid), yield: 1 〇. /0. MS m/z (ESI): 527 [M+l] NMR (400 MHz, DMS0-i/6, ppm): δ 7. 92 (d, / = 8 8 Hz 1H), 7.36 (in, 7H ), 7.22 (d, / = 8. 4 Hz, 1H), 5.46 (d, /= 18.4 Hz, 1H), 5.04 (d, J- 18.4 Hz, 1H), 4.03 (s 3H), 3.82 (s, 3H), 3.14 (m, 4H), 1.98 (s, 3H), 1.91 (m, 4H), 1.36 (s, 9H) Example 59 1-(3-tert-butyl-4-decyloxy-5-琳琳phenyl)-2-(7-imino-2-methyloxy-5-methyl-5-phenyl ratio slightly [3, 4-/?] ° ratio °-6-based Ethyl ketone hydrobromide

59

95255 219 201242964 First Step 1-(3-tert-Butyl-4-decyloxy-5-morpholinylphenyl)-2-(7-iminoamino-2-methoxy-5-mercapto-5 -Phenylpyrazine[3,4-do]D ratio °_6_base) B_) Hydrogenate will be 2-decyloxy-5-mercapto-5-phenyl-6-Herpyrrole [3, 4-ύ] pyridine-7-imine 58f (253 mg, 1 mmol) and 2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholinylphenyl)ethanone 2h (444 mg, 1.2 mmol) was dissolved in 4 mL of tetrahydrofuran, and triethylamine (〇· 166 mL, 1.2 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 7-Imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-indolylpyridin-6-yl)ethanone hydrobromide 59 (12 mg, light yellow Solid,) Yield: 19.3%. MS m/z (ESI): 543 [M+1] H NMR (400 MHz, DMSO-i/e, ppm): δ 7. 96 (d, /= 8.8 Hz, 1H), 7.38 (m, 7H) , 7.25 (d, / = 8. 4 Hz, 1H), 5.53 (d, /= 18.8 Hz, 1H), 5. 10 (d, /= 18.8 Hz, 1H), 4.06 (s, 3H), 3.88 ( s, 3H), 3.80 (m, 4H), 3.03 (m, 4H), 2.13 (s, 3H), 1.36 (s, 9H) Example 60 1-(3,5-di-tert-butyl-4-hydroxyl Phenyl)-2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3,4-/?]pyridin-6-yl)ethanone hydrobromide Salt 95255 220 201242964

The first step is 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(7-imino-2-indolyl Φ-5-methyl-5-phenyl-pyrrole [ 3, 4-dosed]pyridin-6-yl)ethanone hydrobromide salt 2-methoxy-5-mercapto-5-phenyl-6 and the ratio σ[3, 4,Z?]0 〇定定-7-imine 58f (64 mg, 0.25 mmol) and 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone lf (248 mg, 0.76 mmol) were dissolved in To 2 mL of sterol, triethylamine (〇. 105 mL, 0.76 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Amino-2-methoxy-5-mercapto-5-phenylpyrolo[3,4-/?]σ ratio -6-yl)ethanone hydrobromide 60 (30 mg, yellow solid) , yield: 23.8%. MS m/z (ESI): 500 [M+l]. NMR (400 MHz, DMSO-^b, ppm): δ 7. 95 (d, /=8. 4 Hz, 1H), 7. 69 ( s, 2H), 7. 39(m, 5H), 7. 25(d, /=8. 8 Hz, 1H), 5.43 (d, /=18.4 Hz, 1H), 5.06(d, /=18.4 Hz , 1H), 4.04 (s, 3H), 1.98 (s, 3H), 1.40 (s, 18H) Example 61 l-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl) Phenyl]-2-(7-imino 221 95255 201242964 -2-decyloxy-5-mercapto-5-phenyl-pyrrolo[3,4-/?]° pyridine-6-yl Ethyl ketone hydrogen oxalate

First Step _ 1-[ 3-tert-Butyl-4-decyloxy-5-(1-bunkyl)phenyl]imino-2-indolyl-5-mercapto-5-phenyl -pyrrolo[3,4-doe>pyridin-6-yl)ethanone hydrobromide salt 2-methoxy-5-indolyl-5-phenyl-6#-0 ratio [3 , 4-doing &gt; pyridine-7-imine 58f (253 mg, 1 mmol) and 2-bromo-M3-tert-butyl-4-decyloxy-5-U-piperidinyl)phenyl]ethanone 12b (441.6 mg, 1.2 mmol) dissolved

The reaction was stirred for 12 hours in 3 mL of N,N-didecylguanamine. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium sulfate solution (10 mL×3), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Chromatography to purify the residue obtained by eluent system A to give the title product 1-[3-tert-butyl-4-methoxymethyl)phenyl]-2-(7-imino-2-methoxy) -5-5-nonylphenyl _ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 MS m/z (ESI): 541 [M+l] 95255 222 201242964 *H NMR (400 MHz, DMSO-i/e, ppm): δ 9. 96 (s, 2H) 7 94 (d /= 8.8 Hz , 1H), 7.49(s, 1H), 7.45(s, 1H), 7.37(m 5jj) 7. 22(d, /:8.4 Hz, 1H), 5. 45(d, &gt;18.4 Hz, 1H), 5 〇7 (d /=18. 4 Hz, 1H), 4. 04(s, 3H), 3. 94(s, 3H), 2 9〇(m 4H) 1.91(s, 3H), 1.70 (m, 4H), 1.54 (m, 2H), i.34 (s 9H) Example 62 2-[ [3-tert-butyl-5-[2_(7-imino-2-yloxy) -5-Methylphenyl-pyrrolo[3,4-yl]pyridin-6-yl)ethinyl]-2-methoxyphenyl]amino]# acetonitrile hydrobromide

The first step 2-[[3-tert-butyl-5-[2-(7-imino-2-methoxy-5-methyl-5-phenyl-pyrrolo[3, 4-do] Bis- 6-yl)ethinyl]-2-nonyloxyphenyl]amino] acetonitrile hydrobromide 2-oxooxyindenyl-5-phenyl each [3, 4-/ ???0-0-imine 58f (253 mg, 1 mmol) and 2-[[5-(2-oxaethyl)-3-tert-butyl-2-decyloxyphenyl]amino] acetonitrile 14b (406.8 mg, 1.2 mmol) was dissolved in 3 mL of N,N-didecylguanamine and stirred for 12 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). EtOAc EtOAc EtOAc EtOAc EtOAc Column chromatography Chromatography of the obtained residue to give the title product 2-[[3-(4-(4-amino-5-[2-(7-i-amino-2-yloxy-5-methyl) -5-Phenyl-pyrrolo[3,4-yl]pyridin-6-yl)ethinyl]-2-methoxyphenyl]amino]acetonitrile arbromo broth 62 (150 mg, pale yellow solid) , yield: 25.3%. MS m/z (ESI): 512 [M+l], NMR, NMR, DMSO, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> , 7. 10(d, /=6.8 Hz, 1H), 6. 09(t, /=6. 8 Hz, 1H), 5. 50(d, / = 18. 8 Hz, 1H), 5. 05 (d, /= 18.8 Hz, 1H), 4. 38 (d, /=7.2 Hz, 2H), 4. 03 (s, 3H), 3.72(s, 3H), 1.99(s, 3H), 1.36(s, 9H) Example 63 1-(3-tert-Butyl-4-methoxy-5-morpholinylphenyl)-2-(3-imino-1-indolyl-1-phenyl Compared with each [3, 4-Z?]啥琳-2-yl) ethyl ketone hydrogen oxalate

First step 224 95255 201242964 1-phenyl-1-(3-quinoline)ethanol

3-bromo-quinoline 63a (20·0 g, 96.6 mmol) was dissolved in 120 mL of diethyl ether, and a solution of 2.5 M n-butyllithium (42.5 mL, 106 ramol) in n-hexane was added dropwise. The reaction was stirred for 1 hour and acetophenone (12.4 mL, 106 mmol) was then weighed. 50 mL of a saturated ammonium chloride solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (5 mL mL 3). The organic phase was combined, washed with saturated sodium chloride solution (2 〇mL×3), dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut , yield: 38. 8 〇 / 〇. MS m/z (ESI): 250 [M+l].H NMR (400 MHz, CDCh, ppm): δ 8. 90 (s, 1H), 8. 24 (s, 1H), 8.11 (m, 1H) ), 7.73 (m, 1H), 7.60 (ra, 1H), 7.57 (m, 1H), 7.50 (ra, 2H), 7.40 (m, 2H), 7.37 (m, 1H), 2. 12 (s, 3H) The second step • 3~(1-azido-1-phenyl-ethyl) 噎 冰 ice bath, 1-phenyl_1_(3-quinolin) ethanol 6 (7. 〇g, 28 mmol) and sodium azide (5 5 g, 84 mmol) were dissolved in 35 mL of water, 35 mL of concentrated hydrochloric acid was added dropwise, and the reaction was stirred for 12 hours. To the reaction mixture, 450 mL of a saturated sodium hydrogencarbonate solution was added to adjust the pH to 7 to 8, and the aqueous phase was extracted with ethyl acetate (15 mL mL). The organic phase was combined, washed with saturated sodium carbonate solution (50 mL×3), dried over anhydrous sodium sulfate The filtrate was filtered, and the filtrate was evaporated to dryness. , light yellow oil), yield 95255 225 201242964 rate: 88. 3 ° / 〇. NMR NMR (400 MHz, CDCb, ppm): δ 8. 82 (s, 1H), 8. 24 (s, 1H), 8.13 (d, /= 8. 8 Hz, 1H), 7.88 (d, / = 8. 0 Hz, 1H), 7.77 (t, /= 8. 8 Hz, 1H), 7.63 (t, / = 8. 0 Hz, 1H), 7.43 (m, 5H), 2. 19 (s, 3H The third step is 3-(1-azido-1-phenyl-ethyl)quinoline 1-oxide 3-(1-azido-1-phenyl-ethyl)quinoline 63c (6.2 g , 22. 6 mmol) was dissolved in 60 mL of dioxane, and m-chloroperoxybenzoic acid (4.8 g, 2 7 mino 1) was added to give the reaction for 3 hours. Add 5 mL of saturated sodium bicarbonate solution to the reaction mixture. The aqueous phase is extracted with dioxane (50 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (2 〇mL×3), dried over anhydrous sodium sulfate, filtered, filtrate The residue was purified by EtOAc (EtOAc) elut elut g,Yellow oil), Yield: 91.0%. MS m/z (ESI): 291 [M+l] NMR (400 MHz, CDCh, ppm): δ 8.70 (d, / = 8. 0 Hz, 1H), 8.49 (s, 1H), 7.91 (d , / = 8. 0 Hz, 1H), 7.85 (s, 1H), 7.78 (t, /= 8.0 Hz, 1H), 7.69 (t, / =: 8.0 Hz, 1H), 7.45 (in, 5H), 2. 15 (s, 3H) Step 4 3-(1-azido-1-phenyl-ethyl)-quinoline-2-carbonitrile 3-(1-azido-1-phenyl-ethyl Quinoline 1-oxide 63 (1 (5. 95 g, 20 mmol) was dissolved in 12 mL of acetonitrile, and cyanotrimethylsulfonium 226 95255 201242964 alkane (4.65 mL, 35 mmol) and diammonium carbamide were added. Gas (2 82 mL, 30 mmol), and stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc) The organic phase was washed with a saturated sodium chloride solution (2 mL mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (1-azido-1-phenyl-ethyl)-quinolin-2-carbonitrile 63e (3.3 g, pale yellow oil), yield: 54·1%. Φ MS m/z (ESI): 300 [M+l] NMR (400 MHz, CDCI3, ppm): δ 8. 65 (s,1H),7· 87 (m, 4H), 7.45 (ra, 5H), 2.34 (s, 3H) Step 5 1_曱基_1_phenyl_2#-σ ratio咯[3, 4-do] 啥琳-3-imine dissolved 3-(1-laminated-1-phenyl-ethyl)-phthalene-2-carbonitrile 63e (2 1 g 7mmol) in 100mL In tetrahydrofuran, mL. 5 mL of water and triphenylphosphonium phosphine (3.68 mL, 14 mmol) were added to stir the reaction for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography using eluent column chromatography. The title product 1_mercapto-1-phenylpyrano[3,4-Z?]fluorene-3-imine 63f (1.6 g, pale-yellow solid). Yield: 83. 5%. 400 MHz, CDCh, ppm): δ 8. 53(s, 1H), 8. I3(m ^ 8.07(m, 1H), 7.69(m, 1H), 7.60(m, 1H), 7.59(m gjj) 7.30(ra, 2H), 7.19(m, 1H), 6.82(s, 2H), 1.82(S) m Step 6 1-(3-tert-Butyl-4-decyloxy-5-morpholinylphenyl -2-(3-imino95255 227 201242964 -1-phenyl-pyrrolo[3,4-Z?]quinolin-2-yl)ethanone hydrobromide 1-methoxy-1 -phenyl-2 and-pyrrolo[3,4-W quinolin-3-imine 63f (273 mg, 1 mmol) and 2-di-1-(3-tert-butyl-4-decyloxy-5-琳琳phenyl) ethyl ketone 2h (444mg, 1.2mmol) dissolved in 5mL 曱To a mixed solvent of an alcohol and tetrahydrofuran (V/V = 3:2), triethylamine (0.16 mL, 1.2 mmol) was added, and the reaction was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -(3-imino-1-fluorenyl-1-phenyl-pyrrolo[3,4-oxa]quinolin-2-yl)ethanone hydrobromide 63 (120 mg, pale yellow color solid) , Yield: 18. 7 ° / 〇. MS m/z (ESI): 563 _] WNMRUOO MHz, DMSO-ice, ppm): δ8·29 (ιη, 12H), 5. 60 (d, /=18. 0 Hz, 1H), 5.19 (d , /=18.0 Hz, 1H), 3.95 (s, 3H), 3.80 (m, 4H), 2.99 (m, 4H), 2. 12 (s, 3H), 1.36 (s, 9H) Example 64 l- [3-tert-Butyl-4-decyloxy-5-U-piperidinyl)phenyl]-2-(3-imino-1-methyl-1-phenyl-pyrrolo[3, 4 -Z?]quinolin-2-yl)ethanone hydrobromide

228 95255 201242964 First Step 1-[3-tert-Butyl-4-decyloxy-5-(1-Bentyl) Styrene]-2-(3-imino-1-indenyl-1- Phenyl ratio of 11 and [3, 4-/?] quinolin-2-yl) ethyl ketone hydrobromide salt 1-mercapto-1-phenyl-2 and - indolo[3, 4-啥琳-3-imine

63f (273 mg, 1 mmol) and 2-bromo-1-[3-tert-butyl-4-decyloxy-5-(piperidinyl)phenyl]-ethanone 12b (441.6 mg, 1.2 mmol) were dissolved in The reaction was stirred for 12 hours in 3 mL of N,N-didecylguanamine. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained by purifying the eluent system A gave the title product 1-[3-tert-butyl-4-decyloxy-5-(1-piperidinyl)phenyl]-2-(3-imine)曱-1-fluorenyl-1-phenylpyrolo[3,4-Z?]indol-2-yl)ethyl hydrobromide 64 (160 mg, pale yellow solid), yield: 25·0 %. MS m/z (ESI): 561 [M+l] _ H R (400 MHz, DMSO-i/e, ppm): δ 8. 64 (s, 1H), 8· 28 (m, 1H), 8. 15(m, 1H), 7. 97 (m, 1H), 7.80 (m, 1H), 7.39 (m, 7H), 5.56 (d, /=18.4 Hz, 1H), 5.06 (d, /= 18.4 Hz, 1H), 3.94(s, 3H), 2.93 (m, 4H), 2.11(s, 3H), 1.7〇(m, 4H), 1.53 (m, 2H), 1.34 (s, 9H) 65 N-[3-tert-butyl-5-[2-(7-imino-2, 5-didecyl-5-phenyl-pyrrolo[3,4-do]&gt;-pyridyl-6- Ethyl)-2-methoxyphenyl]acetamide hydrobromide 229 95255 201242964

First step N-[3-tert-butyl-5-[2-(7-iminoamino-2,5-dimethyl-5-phenyl-pyrrolo[3,4-Z?]pyridine-6 -yl)ethinyl]-2-nonyloxyphenyl]acetamidine hydrobromide 2,5-dimercapto-5-phenyl-6 and -pyrrolo[3,4-Z?] Pyridine-7-imine 9f (237 mg, 1 mmol) and N-[5-(2-bromo-ethenyl)-3-tert-butyl-2-decyloxyphenyl]ethanoamine 13b (410.4 mg, 1.2 mmol) was dissolved in 3 mL of N,N-dimethylguanamine and stirred for 12 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography The residue obtained was purified using eluent (EtOAc) to afford the title product N-[3-tert-butyl-5-[2-(7-iminoamino-2, 5-didecyl-5-phenyl- Pyrrolo[3,4-/?]pyridin-6-yl)ethinyl]-2-methoxyphenyl]acetamide hydrobromide 65 (120 mg, pale yellow solid), yield: 20. 7%. MS m/z (ESI): 499 [M+l]^ NMR (400 MHz, DMSO-form, ppm): δ 10.20 (factory s, 1H), 9.74 {br. s, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.96 (d, 230 95255 201242964 / = 8. 4 Hz, 1H), 7. 69 (d, / = 〇Hz, 1H) 7 62 (d h2.〇Hz,110, 7.37 0η,5H),5.45(d,/: at 8 Hz, no, 5.〇8(d,/=18.8Hz,ih), 4.12(s,3H),2 64 (s' 3H),2.11 (s , 3H), 2.00 (s, 3H), i37 (s 9H) 'Example 66

L-[3-tert-butyl-4-decyloxy-5-(2-oxa, 6-azaspiro[3. 3]hexyl)phenyl]-2-(5,,6,- Diethoxy water fluoride _3' _imino _ spiro [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl) ethyl ketone hydrobromide

φ 1-[3-tert-Butyl-4-decyloxy-5-(2-oxa-6-azaspiro[3. 3]hex-6-yl)phenyl]-2-(5', 6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropanol -1,1'-isoindole]-2'-yl)ethanone hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3,-iso η 卜 朵 ·]-1'-imine 41g (134mg, 〇.51imnol) and 2-bromo-1-[3-tert-butyl-4-decyloxy-5-(6-oxa-2-azaspiro[3. 3]heptan-2-yl)phenyl]ethanone 40f (202 mg, 0.53 mmol) was dissolved in 2 mL of tetrahydrofuran, triethylamine (0.lmL, 0. 72 mmol) was added, and the reaction was stirred for 12 hours. Filtration, 遽 cake with n-hexane (10 mL) and water (10 mL x 3), dried in vacuo to give the standard 231 95255 201242964

''Fluoro-3'-imino-spiro-bromide 66 (108 mg, [cyclopropanone-1,1'-isoindoline]-2'-yl)ethanone hydrochloride acid salt yellow solid) , Yield: 32.9%. MS m/z (ESI): 566 [M+l] 4 NMR (400 MHz, DMS 〇-' ppm): δ 9. 31 (z?rs 1H) 9. 03 (Z?/*· s, 1H) , 7. 41 (d, = 2. 0 Hz, ih) 7 07 (d / - 2. 0 Hz, 1H), 7. 02 (s, 1H), 5. 17 (s, 2H), 4. 74 (m, 4H), 4. 23 (q, /= 7.2 Hz, 2H), 4. 12 (q, / = 7 2 Hz 2H), 3.99 (m, 4H), 3.67 (s, 3H), 1.77 ^ 2R); 1 &lt; 65 (m, 2H), 1.40 (t, / = 7.2 Hz, 3H), 1.37 (s, 9H), 131 (t, / = 7.2 Hz, 3H) Example 67 l-[3- tert-Butyl-4-methoxy-5-[(i especially 55&gt;)_8_oxa-3-azabicyclo[3.2.1]oct-3-yl]phenyl]-2-(5' ,6'-diethoxy-fluoro_3'-Asia

First step 95255 232 201242964 l-[3-tert-Butyl-4-methoxy-5-[(i疋,55)-8-oxa-3-azabicyclo[3.2.1]-- 3-yl]phenyl]_2-(5,6, _diethoxy_4,-fluoro-3, _imino-spiro[cyclopropane-1,1'-isoindolin]_2' -yl)ethanone hydrobromide salt 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-oxime, 3, oxaisoporphyrin]-indole-imine 41g (156mg, 56. 56mmol) and 2-bromo-l-[3-tert-butyl-4-methoxy-5-[(1 especially 550-8-oxa-3-azabicyclo[3.2.1] octyl -3-yl]benzyl]ethanone 39g (250mg, 〇.63mmol) was dissolved in 5mL of tetrahydrofuran, and triethylamine (〇·10 mL, 〇. 72 mmol) was added, and the reaction was stirred for 12 hours. Concentration by pressure, the residue obtained was purified by EtOAc EtOAc (EtOAc) 3-Azabicyclo[3·2·1]oct-3-yl]phenyl]-2-(5,6, _diethoxy-4'-fluoro-3'-imino-spiro[ Cyclopropane-1,1,-isoporphyrin]-2'-yl)ethanone hydrobromide 67 (102 mg, pale yellow solid), yield: 26.1% MS m/z (ESI): 580 [M+l] 4 NMR (400 MHz, DMSO-忒, Ppm): 7. μ (d, 1.6 Hz, • 1H), 7. 57 (d, /=1.6 Hz, 1H), 6. 98 (s, 1H), 5. 22 (s, 2H), 4. 41 (m, 2H), 4. 22 (q, /= 7. 2 Hz, 2H), 4. 11 (q, Ί.2 Hz, 2H), 3.91 (s, 3H), 3.12 (d, J= 10.5 Hz, 2H), 2.88 (d, /= 10.5 Hz, 2H), 2.07 (m, 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.58 (m, 2H), 1.40 (t, /= 7.2 Hz, 3H), 1.38 (s, 9H), 1.30 (t, / = 7.2 Hz, 3H) Example 68 l-[3-tert-butyl-4-methoxy-5-(morpholine-1) 4_carbonyl)phenyl]_2_(5,6-diethoxy-4-1-3-imino-1,1-dimethyl-isoindoline-2-yl)ethyl 233 95255 201242964 ketone hydrogen Bromate

The first step, 1-tert-butyl-2-methoxy-benzene, 2-tert-butyl-benzene 2a (15 g, 100 mmol) was dissolved in 200 mL of acetone, potassium carbonate (20.70 g, 150 mmol) and The carrageenan (21 g, 150 mmol) was stirred for 12 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) . Step 2 3-tert-Butyl-2-decyloxy-benzofural Under ice bath, 1-tert-butyl-2-methoxy-benzene 68a (12. 50 g, 76111111〇1) and 1^ ,1'^',? ^-tetradecylethylenediamine (12.40 bogey, 107111111〇1) 234 95255 201242964 Dissolved in 200 mL of methyl tert-butyl ether, dropwise 2.5 Μ n-butyllithium (33·40 mL, 84 mmol), room temperature The mixture was stirred for 2 hours, and hydrazine, hydrazine-dimercaptocarboxamide (16.60 g, 228, 1 〇1) was added dropwise at 0 ° C, and the reaction was stirred for 2 hours. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography of the residue obtained from EtOAc EtOAc (EtOAc) %. _ MS m/z (ESI): 193.1 [M+1] Step 3 3-tert-butyl-2-decyloxy-benzoic acid 3-br-butyl-2-decyloxy-benzene Furfural 68b (8·30 g, 43.20 mmol) was dissolved in 1 mL of acetonitrile, and 5 mL of sodium hydroxide (3.80 g '95 mmol) in water and tetrabutylammonium bromide (695 mg, 2.20 mm) were added. 〇l), potassium permanganate (8.90 g, 56.20 mmol) was added in portions, and the reaction was stirred at room temperature for 2 φ. Under ice bath, a 5% sodium thiosulfate solution was added to the reaction mixture until the reaction mixture was dark reddish. Add 200 mL of 1 M hydrochloric acid, extract with ethyl acetate (250 mL×2), and combine the organic phases and wash with saturated sodium chloride solution (丨〇 〇mLx2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product: 3-tert-butyl-2-indoxy-benzoic acid 68c (5. 85 g, white solid), yield: 65.0%. The fourth step (3-tert-butyl-2-methoxy-phenyl)-morpholinyl-benzophenone 3-tert-butyl-2-methoxybenzoic acid 68c (632 mg, 3·〇4 mm 〇i) 235 95255 201242964 Dissolved in 10 mL of dichloromethane, adding 1-hydroxybenzotriazole (432 mg, 3. 20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide The amine hydrochloride (613 mg, 3. 20 mmol) was stirred for 10 min, then morpholine (265 mg, EtOAc EtOAc) 5 mL of water was added to the reaction mixture, and the mixture was extracted with dioxane (5 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system B. The title product (3-tert-butyl-2- methoxy-phenyl)- hydrazin-benzophenone 68d (650 mg, m. The fifth step is φ 2-bromo-1-[3-tert-butyl-4-transyl-5-(morphinyl-4-carbonyl)phenyl]ethanone. Dissolving triclosan (133 mg, 1 mmol) in In 2 mL of methane, add 2-bromoethyl bromide (ll 〇 mg, 0.55 mmol), and then add 2 mL of (3-tert-butyl-2-decyloxy-phenyl)-morpholinyl-benzene. The ketone 68d (139 mg, 0.50 mmol) in dioxane solution was stirred for 12 hours. 5 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL×2). The organic phase was combined, washed with saturated sodium carbonate solution (2 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by a solvent system B to give the title product 2-di-1-[3-tert-butyl-4-ylidene-5-(?-m-~~~~~~~~~~~~~~~~~~~ 68e (71 mg, red oil), yield: 39. 〇%. MS m/z (ESI): 384.1 [M+l] NMR (400 MHz, CDCh, ppm): δ 11.57 (s, 1H), 8.06 (d, /= 2.0 Hz, 1H), 7,87 (d , / = 2.0 Hz, 1H), 4.37 (s, 2H), 3.82 (m, 8H), 1.48 (s, 9H) Step 6 236 95255 201242964 2-Bromo-l-[3-tert-butyl-4- Methoxy-5-(morpholinyl-4-carbonyl)phenyl]acetamidine 2-bromo-l-[3-tert-butyl-4-yl-5-(morphinyl-4-yl) Phenyl]ethanone 68e (30 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran, and 0.5 inL of a solution of hydrazine in diethyl ether was added dropwise, and the reaction was stirred for 2 hours. 2 mL of ice water was added to the reaction mixture, and the extract was separated. The organic phase was washed with saturated sodium chloride solution (2 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin-layer chromatography chromatography. The residue was obtained to give the title compound: m-br-bromo-t-butyl-4-methoxy-5-(l-l- yl) 9%. Step 7 1-[3-tert-Butyl-4-methoxy-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3- Imino-1,1-dimercapto-isoindoline-2-yl)ethanone hydrobromide salt 5,6-diethoxy-7-H 3-didecyl-iso-π The amine 24d _ (19. 70 mg, 0.08 mmol) was dissolved in 0. 5 mL of N,N-dimercaptoamine. Add 2-bromo-l-[3-tert-butyl-4-decyloxy- 5-(Merminyl-4-carbonyl)phenyl]ethanone 68f (30 mg, 8.0 mmol) was stirred for 12 hours. 2 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL×2), and the organic phase was combined and dried over anhydrous magnesium sulfate, and the residue was concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography. To give the title product 1-[3-tert-butyl-4-decyloxy-5-(morphin-4-yl)phenyl]-2-(5,6-ethoxy-4-thio- 0%。 Imino-1-, I-monomethyl'-iso-sigma-indolyl-2-yl) ethyl ketone hydrobromide 68 (13 mg, white solid), yield: 26.0%. </ RTI> </ RTI> <RTIgt; d, / = 2. 2 Hz, 1H), 7.90 (d, / = 2. 0

Hz, 1H), 7.44(s, 1H), 5. 44 (s, 2H), 4. 25 (ra, 2H), 4. H (m, 2H), 3. 85 (s, 3H), 3. 70 (m, 4H), 3.58 (in, 2H), 3.20 (in, 2H), 1. 51 (s, 6H), 1.42 (m, 3H), 1. 38 (s, 9H), 1. 29 ( m, 3H) Example 69 1-[3-tert-Butyl-5-(1-alkyl-1-indolyl-ethyl)phenyl]-2-(5,6-diethoxy-4- Fluoro-3-imino-1,1-diindenyl-iso-p-[丨琳-2-yl)ethanone hydrobromide

The first step of 3-tert-butyl-5-methoxycarbonyl-benzoic acid will be 5-tert-butylbenzene-1,3-dibenzoic acid 69a (12 g, 54 with 〇1) and 238 95255 201242964 concentrated sulfuric acid (2mL, cat.) dissolved in 360mL tetrahydrofuran and 曱·(ν/ν = 1〇:1) mixed solvent, 8 (rc stirred reaction for 4 hours. The reaction solution was concentrated under reduced pressure, gelatin filtered, with a rubber hose The residue was purified by column chromatography eluting with EtOAc EtOAc (EtOAc: EtOAc EtOAc 3% MS m/z (ESI): 237.2 [M+l] Step 2 3-tert-Butyl-5-(decyloxy(fluorenyl)aminoindenyl) benzoic acid oxime ester • 3 1-tert-butyl-5-nonyloxycarbonyl-benzoic acid 69b (2.85 g, 12 mmol) was dissolved in 16.4 mL of gasified sulfoxide, and stirred at 85 ° C for 2 hours. mL of dioxane, followed by N_mercaptomethylamine (1.87 g, 19.20 curry 1) and N,N-diisopropylethylamine (6 3 mL, 36 mmol), and stirred at room temperature. The reaction solution was concentrated under reduced pressure. ethyl acetate (50 mL) was evaporated. The filtrate was concentrated under reduced pressure to give the crude title product: 3-t-butyl </ </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 6% MS m/z (ESI): 280.1 [m+1] Step 3 1-[3-tert-butyl-5-(1-hydroxy-l-methyl-ethyl)phenyl]ethanone The crude 3-tert-butyl-5-(decyloxy(methyl)aminoindenyl) benzoic acid oxime ester 69c (2.86 g, 10.25 mmol) was dissolved in 42 mL of tetramine. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 5 'Extracted with ethyl acetate (i 〇〇 mL×2), EtOAcjjjjjjjjjjjjjjjjjjjjjjj 1-[3-tert-Butyl-5-(1-hydroxymethyl-ethyl)phenyl]ethanone 69d (〇.38 g, orange liquid), yield: 15 8%. MS m/z (ESI) : 235.2 [M+l] Step 4 2-Bromo-l-[3-tert-butyl-5-(1-hydroxy-i-methyl-ethyl)phenyl] Ethyl ketone 1-[3-tert-butyl-5-(1-hydroxy-1-methyl-ethyl)phenyl]ethanone 69d (420 mg, 1.79 mmol) and phenyltrimethylammonium tribromide (672 mg, 1.79 mmol) was dissolved in 42 mL of tetrahydropyrene, and the reaction was allowed to stand for 3 hours and allowed to stand for 12 hours. 5 毫升 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B. The title product 2-bromo-l-[3-tert-butyl_5-(p-hydroxy-hydrazinyl-ethyl-ethyl)ethyl]ethanone 69e (287 mg, yellow oil). %. MS m/z (ESI): 315.0 [M+l] Step 5 l-[3-tert-butyl-5-(1-alkyl-1-indolyl-ethyl)phenyl]_2_(5, 6 _Diethoxy-4-H-3-imino-1,1-dimethyl-isoindoline-2-yl)ethanone hydrobromide 5,6-diethoxy-7 -Fluoro-3,3-dimethyl-isoindole-p-amine 24d (85mg, 0.32mmol) was dissolved in 3mL N,N-dimethyl decylamine, added 2-di-l-[3-un Butyl-5-(1-alkyl-1-methyl-ethyl)phenyl]ethanone 95255 240 201242964 69e (100 mg, 0. 32 mmol). 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phase was combined, dried over anhydrous sulphuric acid, and the residue was concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography. To give the title product 1-[3__tert-butyl-5-(1-carboxy-1-methyl-ethyl)phenyl]-2-(5,6-diethoxyi-4-fluoro-3-imine Base-1,1-dimercapto-isoindol-2-yl)ethyl hydrazide 69 (61 mg, yellow solid), yield: 38.4%. &quot;&quot;

MS m/z (ESI) 499.3 [M+l] 4 R (400 MHz, DMSO-i/e, ppm): δ 9 37 [br in, a. 〇i kul, 8 08 (br, 1H), 7. 97 (s' 1H), 7. 89 (d, /= i· 5 Hz, 2H) γ 47 (s, 1H), 5.47(s, 2H), 5. 25 (s, 1H), 4.30- 4.24 (^ 2H) 4. 16-4. 11 (m, 2H), 1.50 (s, 9H), 1.45-1.41 (m ' 3 ' 1.31 (s, 6H), 1.34-1.30 (m, 3H) ' ' Example 70 l-[3-tert-Butyl-5-(1-hydroxy-1-indolyl-ethyl)phenyl]_2, (5, &amp; diethoxy-4'-fluoro-3' - Imino-snail [cyclopropane-hydrazine, hydrazine, ~isoindole]-2 _yl)ethyl-hydrobromide

95255 241 201242964 First step 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(5,6,-diethoxy-4,-fluoro-3'-imino -spiro[cyclopropane-oxime, hydrazine, -isoporphyrin]_2,-yl)ethanone oxime bromide 5',6'-diethoxy_7'-fluoro-spiro[cyclopropane-oxime] , 3, _isoporphyrin]-1'-imine 41g (91mg, 〇. 35mmol) and 2-bromo-l-[3-tert-butyl-5-U-hydroxy-1-methyl-ethyl Phenyl]ethanone 69e (1 〇 8 mg, 〇. 35 mm 〇 1) was dissolved in 2 mL of THF, and then triethylamine (5 mM, EtOAc) was stirred. Filtration of the 'filtrate under reduced pressure' was purified by thin-layer chromatography eluting with EtOAc (EtOAc) to afford title product: </RTI> </RTI> tert-butyl-5-(1-hydroxy-1-indolyl-ethyl)benzene 2-(5,6,6-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]_2, _yl) Ketohydrobromide 70 (22 mg, yellow solid), yield: 11 〇〇. MS m/z (ESI): 497.3 [M+l] &quot;H NMR (400 MHz, DMSO-d/6, ppm): δ 9.43 (br, 1H), 9.06 (br, 1H), 7.90 (s, 1H) ), 7.88 (s, 1H)' 7.83 (s, 1H), 7.03 (s, lH), 5.23 (s, 2H), 4.26_4.21 (m, 2H), 4.15-4. 10 (m, 2H) , 2.03-2.00 (m, 2H), 1.66-1.48 (m, 2H), 1.42 (s, 6H), 1.41-1.39 (m, 3H), 1.35 (s, 9H) Example 71 1-[3-( 4-ethenylpyrazine-1-yl)-5-tert-butyl-4~methoxy-phenyl]-2-(5',6'-diethoxy-4'-fluoro-3, -imino-spiro[cyclopropane-li, monoisoporphyrin]-2'-yl)ethanone hydrobromide 95255 242 201242964

First step _ H3-(4-acetoxy-t-yl)-5-tert-butyl-4-yloxy-phenyl] 2 (5,6-diethoxy-4'-fluoro-3 '-Imino-spiral [cyclopropane-ip-iso-conversion]---)-g-g-hydrogenate salt 5,6'-diethoxy-7'-fluoro-spiro[ Cyclopropane_丨,3, _isoporphyrin]-1 -imine 41g (112mg, 〇.27mmol) was dissolved in im[ n, N-dimethylformamide, added to [3-(4- Ethylpiperazine-indenyl)-, tert-butyl 4-methoxyphenyl]-2bromo-ethanone 20c (60 mg, 0·23 mmol) was mixed with φ for 12 hours. 4 mL of saturated sodium chloride solution and 4 mL of ethyl acetate were added to the reaction mixture, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (2 mL×3). The organic phase was combined, dried over anhydrous sulphuric acid, and the mixture was concentrated under reduced pressure. The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) -phenyl]_2-(5,6'-diethoxy-4'-fluoro-3,-imino-spiro[cyclopropane-1,1-isodolin]-2'-yl)B The ketone hydrobromide 71 (14.5 mg, white solid), yield: 7.9%. MS m/z (ESI): 595.4 [M+l] 243 95255 201242964 丽 R (400 MHz, DMSO-form, ppm): δ 7. 64 (s, 1H), 7.54 (s, lH), 7.00 (s) , 1H), 5.19 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 3.98 (s, 3H), 3. 67 (m, 4H), 3. 02 (m, 2H), 2.96 (m, 2H), 2.06(s, 3H), 1.76(m, 2H), 1. 63 (m, 2H), 1.41 (in, 3H), 1. 39 (s, 9H), 1.31 (m, 3H) Example 72 l-[3-(4-Ethylpiperazin-1-yl)-5-tert-butyl-4-decyloxy-phenyl]-2-(5,6-diethoxy 4-fluoro-3-imino-1,1-dimercapto-isoporphyrin

-2-yl) ethyl ketone arborate

First step 1-[3-(4-Ethylpiperazin-1-yl)-5-tert-butyl-4-decyloxy-phenyl]-2-(5,6-diethoxy- 4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-^L-3, 3-Dimercapto-iso-sigma 1°--1_amine 24d (100 mg, 0.24 mmol) was dissolved in 1 mL of tetrahydro-d-propanol, and l-[3-(4-ethyipiperazine-1) was added. 5-yl-tert-butyl-4-methoxyphenyl]-2bromo-ethanone 20c (61 mg, 0.25 mmol). The reaction mixture was concentrated under reduced pressure 244 95255 201242964, and the obtained residue was purified to the titled product 1-[3-(4-ethylhydrazinopiperazin-1-yl)-5- tert-Butyl-4-methoxy-phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2 Ethyl ketone hydrobromide 72 (80 mg, pale yellow solid), yield: 48.5%. MS ra/z (ESI): 597.4 [M+l] NMR (400 MHz, DMSO-' ppm): δ 9. 27 (s, 1H), 8.96 (s, 1H), 7.68 (s, 1H), 7.60 (s,1H), 7.45 (s,1H),5.41 _ (s, 2H), 4. 27 (in, 2H), 4. 13 (ra, 2H), 3. 99 (s, 3H), 3.68 (ra, 4H), 3. 04 (m, 2H), 2.98 (m, 2H), 2. 06 (s, 3H), 1.51 (s, 6H), 1.42 (ra, 3H), 1.40 (s, 9H ), 1.32 (m, 3H) Example 73 tert-Butyl-5-[2-(5,6-diethoxy-4-ox-3-imino-1,i-dimethyl-isoindole) Porphyrin-2-yl)ethinyl]benzoquinone hydrochloride

The first step is 3-ethenyl-5-tert-butyl-benzoic acid vinegar 95255 245 201242964 The crude 3-tert-butyl-5-(methoxy(fluorenyl)amine fluorenyl group is obtained under ice bath. 5小时。 The benzoic acid methyl ester 69c (2. 86g, 10.25minol) dissolved in 42mL of tetrahydrofuran 'drip 5.20mL 3M decyl magnesium bromide in diethyl ether, stirred for 1 hr. Under ice-cooling, 1M hydrochloric acid was added to the reaction mixture to adjust the pH to 3 to 5, and extracted with ethyl acetate (1 〇〇 χ 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatography of the residue obtained by eluent B to give the title product 1-[3-tert-butyl-5-(1-carbyl-1-methyl-ethyl)phenyl] 1%。 Styrene-5-tert-butyl-benzoic acid methyl ester 73a (1.33 g, white solid), yield: 57.1%. MS m/z (ESI): 235.2 [Mil] Step 2 3-(2-bromoethyl)-5-tert-butyl-benzoic acid methylacetate 1-[3-tert-butyl-5-(1) -hydroxy-1-methyl-ethyl)phenyl]ethanone 3-ethylindolyl-5-tert-butyl-benzoate oxime 73a (598 mg, 2.60 inmol) and phenyltrimethyltribromide ( 978 mg, 2.60 mmol) was dissolved in 6 mL of tetrahydrofuran, and the reaction was stirred for 12 hours. 5 〇mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 〇mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography with eluent system B. The residue was purified to give crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal MS m/z (ESI): 313.0 [M+l]. Step 3 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino- i, I_dimethyl 95255 246 201242964 keto-isoindol-2-yl)ethyl phenyl phthalate hydrobromide 5,6-diethoxy-7-fluoro-3, 3- Mercapto-isoindole-b-amine 24d (380 mg, 1.44 mmol) was dissolved in 12 mL of N,N-dimercaptocarbamide and 3-(2-bromoethenyl)-5-tert-butyl-benzene was added. The decyl decanoate 73b (450 mg, 1.44 匪〇 1) was scrambled for 4 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (40 mL×2), and the organic phase was combined, washed with water (2 mL mL) and washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate The white solid was isolated and washed with water (10 mL×2) to give the crude title product 3-tert-l-yl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1 - dimethyl-isoindole-2-yl)ethinyl]methyl benzoate hydrobromide 73c (229 mg, white solid), yield: 27.5%. The fourth step 3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindole-2-yl Ethyl hydrazide] benzoate hydrochloride will be crude 3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imine• quinone, 1_2 Sulfhydryl-isoindole-2-yl) ethyl hydrazide

The acid salt 73c (193 mg, 0.33 mmol) was dissolved in 8 mL of decyl alcohol, and 4 mL aqueous solution of EtOAc (70 mg, 1.67 mmol) was added dropwise, and the reaction was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&& [2-(5,6-Diethoxy-4-fluoro-3-iminoamino-1,1-diindolyl-iso-p-butylene-2-yl)ethinyl]benzoic acid hydrogen Bromate 73 (148 mg, yellow solid), yield: 85.5%. MS m/z (ESI): 483.2 [Ml] 95255 247 201242964 NMR (400 MHz, DMS0~c/6, ppm): δ 13. 37 (s, 1H), 9. 43 (s 1H), 9. 02(s, 1H), 8.43(s, 1H), 8. 27(s, 1H), 8.25(s, 1H), 7.46(s, 1H), 5.56(s, 2H), 4.26(m, 2H) 4.12(m, 2H), 1.52(s, 6H), 1.44 (m, 3H), 1.39 (s, 9H), 1.33 (m, 3H) Example 74 l-[3-tert-butyl-5-( Morpholine_4_carbonyl)phenyl]_2_(5 6_diethoxy 1~dimethyl-isoindoline-2-yl)ethanone hydrochloride

First step 1-[3-tert-butyl-5-(morpholin-4-carbonyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1, 1-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imine) Base_1,1_一曱基_异°引朵琳-2-yl)ethinyl]benzoic acid hydrogenate salt 73 (52rag,0. lmmol) dissolved in 2mL of dichloromethane, add 1 -Hydroxybenzotriazole (14 mg, 0.1 mmol) and 1-ethyl-3-(3-diamidinyl)carbodiimide hydrochloride (38 mg, 〇. 20 匪〇 1), stirring reaction 5小时。 After the morpholine (18mg, 0. 20 with 〇1), stirring reaction 3. 5 hours. The reaction solution was concentrated under reduced pressure, and purified residue purified by EtOAc EtOAc EtOAc EtOAc EtOAc. ] _2 基 基 基 基 基 基 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 74 , white yield), yield: 32. 2%. MS m/z (ESI): 554.3 [M+l], NMR (400 MHz, DMSO-t/e, ppm): δ 9.42 (s, 1H), 9.02 (s, 1H), 8.06 (s, 1H) ), 7.94(s, 1H), 7. 77 (s, 1H), 7.46 (s, 1H), 5.50(s, 2H), 4. 26 (m, 2H), 4. 12 (in, 2H), 3.64 (m, 6H), 3.40 (m, 2H), 1.51 (s, 6H), 1.42 (m, 3H), 1.38 φ (s, 9H), 1.32 (m, 3H) Example 75 3-tert-butyl -N-cyclopropyl-5-[2-(5,6-diethoxy-4-qi-3-imino-1,1-dimethyl]&quot; Benzoylamine

Hirose

First step 3-tert-butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoroimino-M-dimercapto-isoindoline-2- Benzo) phenylhydrazine hydrochloride 3-tert-butyl-5-[2-(5,6-diethoxy-4-IL-3-imino 249 95255 201242964-1, 1-Dimercapto-isoindoline-2-yl)ethenyl]benzoic acid hydrobromide 73 (52 mg, 0·10 mmol) was dissolved in 2 mL of N,N-dimercaptocarbamide and added to the ring. Propylamine (llmg, 0.20 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetradecylurea hexafluorophosphate (46 mg, 0·12 mmol), The reaction was stirred for 2 hours and then N-isobutylpropyl-2-amine (24 mg, 0.24 mmol) was added and the mixture was stirred for 4 hr. To the reaction mixture was added i 〇 mL saturated sodium sulfonate solution, and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by silica gel chromatography using EtOAc EtOAc (EtOAc) --U-dimethyl L-lin- 2-yl)ethinyl]^- a = hydrochloride 75 (13 mg, white solid), yield: 23 2%. MS m/z (ESI): 524.3 [M+l] H NMR (400 MHz, DMS0-i/6, ppm): § 9 (br, 1H), 8.78 (br, 1H), 8.40 (s, 1Ηχ 8&gt ;; ; 8.1KS, 1H), 7.45(s, 1H), 5.51 (s, 2H), ^ m ^ 4.12(, 2H), ,89(ra, 1H), ,52(s, 6H)&gt;1&gt;3 ^ ^ 1.31 (m, 3H), 0.74 (m, 2H), 0.64 (m, 2h) U' 12H)! Example 76 3-tert-butyl-5-[2-(5: [cyclopropanone] -u,-Different, called 2, base) B. Port 95255 250 201242964

First step 3_tert-butyl-5-[2-(5',6'-diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1, oxime-isoindole] Porphyrin]-2'-yl)ethenyl]nonyl phthalate hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-1,3,-isoindole Porphyrin]-1'-imine 41g (395mg, 1.5〇mmol) was dissolved in 12mL of N,N-didecylguanamine and added to 3-(2-bromoethenyl)-5-tert-butyl 5小时。 The base - benzoic acid oxime ester 73b (540mg, 1. 50mmol) '3〇t stirring reaction 1. 5 hours. 100 mL of a saturated sodium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (m.sub.3). The organic phase was combined and washed with saturated sodium sulfate solution (1 mL mL), dried over anhydrous magnesium sulfate and filtered. Concentration under reduced pressure, EtOAc (EtOAc:EtOAc) Imino-spiro[cyclopropane-oxime, ι'-iso. 引.多琳] -2'-yl)ethinyl] decyl benzoate hydrobromide 76a (231 mg, white solid), yield : 26.7%. MS m/z (ESI): 497.3 [M+l]. Step 2 251 95255 201242964 3-tert-butyl-5-[2-(5',6,-diethoxy-4,-fluoro-3, -imino-spiro[cyclopropane-1,1'-isoindoline]-2,-yl)ethenyl]benzoic acid hydrochloride 3-tert-butyl-5-[2-(5 ,6,-Diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1,indole-isoindoline]-2,-yl)ethenyl]benzoic acid formamidine The hydrobromide salt 76a (226 mg, 0.39 mmol) was dissolved in 20 mL of methanol, and 4 mL of an aqueous solution of lithium hydroxide (164 mg, 3.92 mmol) was added dropwise, and the mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc). 2-(5,6,-Diethoxy-fluoro-3'-imino-spiro[cyclopropane_1,1,-isoindoline]-2, yl)ethenyl]phenylhydrazine 0%。 Acidate 76 (136 mg, white solid), yield: 67. 0%. MS m/z (ESI): 483.2 [M+1] H NMR (400 MHz, DMSO-i/e, ppm): δ 9.09 (br, 1H), 8.39 (s, 1H), 8.23 (s, 1H) , 8.14 (s, 1H), 7.03 (s, 1H), 5.38

Cs, 2H), 4.23 (m, 2H), 4. 12 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.41 (m, 3H), 1.34 (m, 12H) 77 2~[[3-tert-Butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-iminophenyldimethyl-isoindol-2-yl)B醯基] stupid]amino]acetonitrile hydrobromide 95255 252 201242964

In the first step 2, 6-dibromo-4-tert-butyl-phenylamine, 4-tert-butylaniline 77a (50 g, 335.60 mmol) was dissolved in 300 mL of dichloromethane, and liquid bromine was added dropwise. 118g, 738. 30mmol), the reaction was stirred at room temperature for 1.5 hours. Under ice bath, add 1 Μ sodium hydroxide solution to the reaction solution to adjust the pH value to 9 to 1 〇, extract the liquid, extract the aqueous phase with dichloromethane (30 mL×3), combine the organic phases, and sequentially use 1 M sodium hydroxide. The solution (30 mL×3), water (30 mL×3) and saturated sodium carbonate solution (30 mL×3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 2, 6-dibromo-4-tert-butyl-aniline 77b (107S, reddish brown liquid), product was subjected to the next step without purification. MS m/z (ESI): 307.9 [M+l] </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; 522. 80mmol) dissolved in 253 95255 201242964 200mL N, N-monomethylamine, 2,6-di-wet-4-tert-butyl-aniline 77b (107g' 348. 50mmol), stirring reaction 12 hours. 400 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL mL). The organic phase was washed with water (100 mL×3) and saturated sodium chloride solution (丨〇〇mL×3), dried over anhydrous magnesium sulfate, filtered and filtered. The liquid was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc ), yield: 79. 2 〇 / 〇. The third step of 1-(3-bromo-5-tert-butyl-phenyl)ethanone dissolves 1,3-dibromo-5-tert-butyl-benzene 77c (10 g, 34.25 mmol) in a dry ice bath 5小时。 The reaction was stirred for 0. 5 hours. Further, n,N-dimercaptoacetamide (4.47 g, 51.37 mmol) was added, and the reaction was stirred for 5 hours. To the reaction mixture, 30 mL of water and 30 mL of a saturated ammonium chloride solution were added, and ethyl acetate was extracted (30 mL×5), and the organic phase was combined, washed with water (3 mL mL 3) and saturated sodium carbonate solution (30 mL×3), dried over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified eluting from EtOAc EtOAc (EtOAc) g, yellow liquid) 'yield: 41.2%. MS m/z (ESI): 255.0 [M+l] </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> (3-bromo-5-tert-butyl-phenyl)ethanone 77d (1.02g, 4mmol), cuprous oxide (60mg, 〇.4〇mm〇l) and cuprous iodide (76mg, 0.40 with 〇1) 95255 254 201242964 dissolved in N-methylpyrrolidone 2. 60mL in 're Add 60 ml of ammonia water and mix the reaction at 110 ° C for 2 hours. To the reaction mixture, 20 mL of water was added, and ethyl acetate (20 mL×3), and the organic phase was combined, washed with water (20 mL×3) and saturated sodium carbonate solution (20 mL×3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by column chromatography eluting with EtOAc EtOAc (EtOAc) %. MS m/z (ESI): 192.1 [M+l] # 5 Step 2_ [(3_Ethyl-5-tert-butyl-yl) Amino] B. 1-(3-Amino- 5-tert-Butyl-phenyl)ethanone 77e (760 mg, 3.98 mmol) was dissolved in 10 mL of N,N-didecylamine, potassium carbonate (825 mg, 5.97 mmol) and 2-bromoacetonitrile (955 mg) , 7. 96mmol), 7〇.搅拌 Stir the reaction for 3 hours. To the reaction mixture, 30 mL of water was added, and ethyl acetate (30 mL×3) was evaporated, and the organic phase was combined with water (15 mL×3) and washed with saturated sodium sulfate (15 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) Yield: 99.9%. MS m/z (ESI): 248.2 [M+18] Step 6 2-[[3-(2-bromoethyl)-5-tert-butyl-phenyl]amino] acetonitrile 2-[( 3-Ethyl-5-tert-butyl-phenyl)amino]acetonitrile (200 mg, 0·87 ιμο1) was dissolved in 25 mL of tetrahydrofuran, and was added in portions to be 255 95255 201242964 bis-indenyl ammonium dibromide (327 mg, 0. 87 mmol), the reaction was stirred for 20 hours. The resulting residue was purified by EtOAc (EtOAc) (EtOAc) Acetonitrile 77 g (95 mg, red liquid), yield: 35.3%. MS m/z (ESI): 310.1 [M+l] Step 7 2-[[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imine) 1,1-dimethyl-isoindolin-2-yl)ethinyl]phenyl]amino]acetonitrile hydrobromide 5,6-diethoxy-7-1-3, 3-Dimercapto-iso-α-bendo-1, amine 24d (77 mg, 0.25 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and 2-[[3-(2-bromoethyl) Amidinosyl-5-tert-butyl-phenyl]amino]acetonitrile 77 g (90 mg, 0.29 mmol) was stirred for 1 hour. Add i〇mL water to the reaction solution, extract with ethyl acetate (10 mL), and combine the organic phase, and then wash with water (10 mL×3) and saturated sodium carbonate solution (10 mL×3), dry over anhydrous magnesium sulfate, filtered, filtrate Concentration under reduced pressure, the residue obtained was purified mjjjjjjjjjj Fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethinyl]phenyl]amino]acetonitrile hydrobromide 77 (35 mg, yellow solid), yield : 21. 1%. MS m/z (ESI): 495.3 [M+l] &quot;H NMR (400 MHz, DMSO-i/e, ppm): 6 9.38 (br, 1H), 8.96 (br, 1H), 7.45 (s, 2H ), 7.21 (s, 1H), 7.12 (s, 1H), 6.52 (t, / = 6.8 Hz, 1H), 5.39 (s, 2H), 4.40 (d, / = 256 95255 201242964 6 8 Hz, 2H) , 4. 25 (m, 2H), 4. 12 (m, 2H), 1. 51 (s, 6H), 1.42 (m, 3H), U (m, 12H) Example 7 8 N_[3_叔Butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropan-1,1'-isoporphyrin]-2 '-yl)ethinyl]phenyl]acetamide hydrobromide

First step, ethyl bromo-tert-butyl-phenyl) ethanoamine 1-(3-amino-5-tert-butyl-phenyl)ethanone 77e (600 mg, 3. Ummol) was dissolved in 15 mL of dioxane. To the alkane, triethylamine (635, 6.28 mmol) was added, and acetonitrile (495 mg, 6.28 mmol) was added dropwise, and the mixture was stirred for 0.5 hr. To the reaction mixture, 30 mL of water was added, and the mixture was extracted with chloroform (20 dl3). The organic phase was washed with water (15 mL×3) and saturated sodium carbonate solution (15 mL×3), dried over anhydrous magnesium sulfate The residue obtained was purified by eluent column chromatography eluting to afford the title product N-(3-ethylamino-5-tert-butyl-phenyl)acetamide 78a (7 mg, yellow liquid). , yield: 95. 6%. 257 95255 201242964 MS m/z (ESI): 234.2 [M+l] Step 2 N-[3-(2-bromoethenyl)-5-tert-butyl-phenyl]acetamide as N-( 3-Ethyl-5-tert-butyl-phenyl)acetamide 78a (200 mg, 〇.86 mmol) was dissolved in 25 mL of tetrahydrofuran, and phenyltrimethylammonium bromide (323 mg, 0. ) 'Stirring reaction for 1 hour. Filtration, hydration and concentration of EtOAc, EtOAc (EtOAc) Acetamide 78b (110 mg, yellow liquid), yield: 41.0%. MS m/z (ESI): 311.1 [Ml]. Step 3 N-[3-tert-butyl-5-[2-(5',6,-diethoxy-4'-fluoro-3,-imine Base-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenyl]acetamide hydrobromide 5',6'-diethoxy-7 '-Fluoro-spiro[cyclopropane-1,3,-isoindoline]-indole-imine 41g (50mg, 0·19mmol) was dissolved in 1.5〇mL tetrahydrofuran, added N-[3-(2 -Bromoethendyl)-5-tert-butyl-phenyl]acetamide 78b (60 mg, 0·19 mmol) was stirred for 3 hours. Filtration gave a white solid which was washed with EtOAc (EtOAc (EtOAc) ,-Imino-spiro[cyclopropyl-1-, Γ-iso-indolyl]-2'-yl)ethinyl]phenyl]acetamide hydrobromide 78 (50 mg, white solid), Rate: 45.9%. MS m/z (ESI): 496. 3 [M+l] 'H NMR (400 MHz, DMSO-ice, ppm): δ 10.16 (s, 1H), 9.44 258 95255 201242964 (br, 1H), 9.06 ( Br, lH), 8.15 (s, 1H), 7.88 (s, 1H), 7. 71 (s, 1H), 7. 03 (Sj iH), 5. 20 (s, 2H), 4. 23 (m , 2H), 4. 12(m, 2H), 2. 07 (Sj 3H), 1.79 (nij 2H), 1.66 (m, 2H), 1· 41 (m, 3H), 1.34 (m, 12h) Example 79 N-[3-tert-m(5,6-diethoxy-4-fluoro-3-imino-1,b-didecyl-isoindoline-2-yl)ethenyl]benzene Acetamine hydrobromide

The first step of monomethyl ketone-2-yl)ethyl hydrazide] phenyl] acetamidine hydrobromide 5, 6-diethoxy _7_ gas _3, 3 dimethyl _Isozhongduo-amine tear (47mg, 0. 18IM01) dissolved in 1mL of tetrahydrofuran 'Add N-[3_(2_bromoethenyl)-5-tert-butyl-phenyl]acetamide 78b (55mg, υ 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 -Ethoxy-4-1-3-imino, bis-indenyl _iso- 嗓 嗓 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , white solid), Yield: 53.9%. MS m/z (ESI): 498.3 [M+l] 'H NMR (400 MHz, DMSO-i/e, ppm): δ 10. 16 (s, 1H), 9 33 (br, 1H), 8.94 (br, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7. 75(s, 1H), 7. 44(s, 1H), 5. 39 (s, 2H), 4.24 (m, 2H), 4. 12 (in, 2H), 2. 08 (s, 3H), 1. 51 (s, 6H), 1. 41 (m, 3H 1.35 (m, 12H) Example 80 3-tert-Butyl-N-cyclopropyl-5-[2-(5,6-diethoxy-4-fluoro_3-imino-1, Dimercapto-isoindoline-2-yl)ethinyl]-2-methoxy Base_benzamide amine hydrobromide

The first step is 5-ethenyl-3-tert-butyl-2-hydroxy-benzoic acid 260 95255 201242964 3-tert-butyl-2-methoxy-benzoic acid 68c (1. 60 g, 7. 7 〇mmQi) was dissolved in 20 mL of dioxane, and acetonitrile (0.72 g, 9.23 mmol) and aluminum trichloride (2.55 g, 19.25 mmol) were added dropwise. The reaction was stirred at 40 ° C for 6 hours. To the reaction mixture, 20 mL of ice water was added, and 100 mL of ethyl acetate was added, and the aqueous layer was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous magnesium sulfate. Filtration, concentration and concentration under reduced pressure, and the solid was crystallized, and the residue obtained was purified by recrystallization from system B to give the title product 5-ethyl-ethyl 3-tert-butyl-2-hydroxy-b. g, gray solid), yield: 62.7 ° / 〇. Step 2 5-Ethyl-3-tert-butyl-N-cyclopropyl-2-yl-p-carbamoylamine 5-ethenyl-3-tert-butyl-2-yl-p-formic acid 8〇&lt;1 20 g 5. 08 mmol) was dissolved in 15 mL of dioxane, and 1-butyryl benzopyrene (720 mg, 5.33 mmol) and 1-ethyl-3-(3-diamine) were added. Propyl)carbodiimide hydrochloride (1.02 g, 5.33 mmol) was dissolved with stirring, and then cyclopropylamine φ (29 mg, 5.08 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj 801) (600, colorless viscous solid), yield: 42.8%. Step 3 5-Ethyl-3-tert-butyl-N-cyclopropyl-2-methoxy-benzoquinone-ethylamine 5-ethylindenyl-3-tert-butyl-N-cyclopropyl- 2-Phenyl-benzoquinone 80b (275 mg, 1 mmol) was dissolved in 3 mL of acetone, and a solution of carbonic acid (2 〇 7 mg, 1. 50 mmol) and iododecane (〇·3 mL, 6 mmol), 4 (TC) Anti-deer 12 small 95255 261 201242964. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified with EtOAc EtOAc. -2-methoxy-benzamide 8 〇c (23 mg, colorless oil), Yield: 79. 0%. MS m/z (ESI): 290.2 [M+l] -(2-bromoethenyl)-3-tert-butyl-N-cyclopropyl-2-decyloxy-benzamide 5 5-ethenyl-3-tert-butylcyclopropyl-2- Methoxy-cobylcarboxamide 80c (230 mg, 0.79 mmol) was dissolved in 3 mL of trioxane, and copper bromide (355 mg, 1.59 mmol) '4 was added (TC was stirred for 12 hours. Transition, filtrate concentrated under reduced pressure The resulting residue was purified by EtOAc EtOAc (EtOAc) Methionine 80d (190mg, white viscous solid), yield: 65. 0° / 〇 MS m/z (ESI): 369.1 [M+l] Step 5 3-tert-butyl-1^-cyclopropane 5-[2-(5,6-diethoxy-4-fluoro-3~imine is -1,1_dimethyl-iso- 0-decyl)-ethyl thiol] -2-decyloxy-p-methylamine hydrobromide 醯 5,6-·-ethoxy-gas _3,3-dimercapto-iso σ π 贱 ~ 贱 (31. 80mg, 0. 12 mmol) was dissolved in 1 mL of tetrahydrofuran, and ς, (2~ ethoxyethyl)-3-tert-butyl-N-cyclopropyl-2-hydroxy-crackamine (44 mg, 0) was added. The reaction was stirred for 12 hours. Filtration gave a white solid, which was washed with EtOAc (EtOAc: EtOAc EtOAc (EtOAc) ~(5,6-Diethoxy-4-fluoro-3-imino-1,1-didecyl-iso-t- porphyrin~2, yl) Ethyl phenyl 2-methoxy-benzene Hydrazine hydrobromide 80 (38 mg, white solid), yield: 5 〇. 〇% MS m/z (ESI): 554. 3 [M+l] NMR (400 MHz, MSO-ppm) : δ 9. 26 (s,1H),8·96 (s, 1H), 8. 51(d, /=4.2 Hz, 1H), 7. 96(d, / = 2. 0 Hz, 1H ), 7. 93( d, / = 2. 0 Hz, 1H), 7. 45 (s, 1H), 5. 41 (s, 2H), 4.26 (m, 2H), 4.13 (m, 2H), 3.83 (s, 3H) , 2.89 • (m,1H), 1.49(s, 6H), 1.42 (m, 3H), 1.40 (s, 9H), 1.31 (m, 3H), 0.73 (m, 2H), 0.60 (m, 2H) Example 81 3_tert-Butyl-1^-cyclopropyl-5-[2-(5',6'-diethoxy-4,-fluoro-3'-imino-spiro[cyclopropane- 1,1'-isoporphyrin]-2,-yl)ethinyl]-2-methoxy-benzoguanamine hydrobromide

81

The first step is 3-tert-butyl-N-cyclopropyl_5_[2-(5,6,-diethoxy-4, -fluoro-3,-imino-spiro[cyclopropane-1, 1,-isoporphyrin]-2,-yl)ethinyl]-2-methoxy 295 95255 201242964 base-benzoguanamine hydrobromide 5',6'-diethoxy-7' -Fluoro-spiro[cyclopropane-1,3,-isoindoline]-1'-imine 41g (44. 50mg, 0.17mmol) was dissolved in 1mL tetrahydrofurfuran 'Add 5--2- Ethyl bromide)-3-tert-butyl-N-cyclopropyl-2-decyloxy-benzamide 80d (62 mg, 0.117 mmol) was stirred for 12 hours. The title product 3-tert-butyl-N-cyclopropyl-5-[2-(5',6) was obtained as the title product (yield: 2 mL×3). ,-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1,-isoindoline]-2'yl)ethenyl]-2-indolyl-曱醯 曱醯 曱醯 氢 氢 氢 。 。 。 。 。 。 。 。. MS m/z (ESI): 552.3 [M+l] 4 NMR (400 MHz, DMSO--, ppm): δ 9.36 (s, 1H), 9·〇6 (s, 1H), 8.51 (d, / = 4. 3 Hz, 1H), 7.88 (s, 2H), 7.02 (s, 1H), 5. 21 (s, 2H), 4. 23 (m, 2H), 4. 12 (m, 2H), 3. 81 (s, 3H), 2.86 (m, 1H), 1.75 (m, 2H), 1.65 (m, 2H), 1.40 (m, 3H)' 1.38 (s, 9H), 1.30 (m, 3H) , 0.72 (m, 2H), 0.60 (m, 2H) Example 82 3-tert-butyl-5~[2_(5,6-diethoxy-4-fluoro-3-imino-1,1 -Dimethyl-isoindolin-2-yl)ethinyl]_n-(2,3-dihydroxypropyl)benzoguanamine hydrochloride 264 95255 201242964

搴Step 1 3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-didecyl-isoindoline-2- Ethyl)-N-(2,3-dihydroxypropyl)phenylhydrazine hydrochloride 3-tert-butyl-5-[2-(5,6-diethoxy-4- Fluoro-3-imino-1,1-monomethyl-iso-sigma-indolyl-2-yl)ethenyl]benzoic acid hydrobromide γ3 (10 mg, 0.20 mmol) was dissolved in 4 mL Ν , Ν-dimethylformamide, plus 3-aminopropanone-1,2-diol (36 mg, 0.40 mmol), 2-(7-azobenzotriazole)-oxime , Ν, Ν,, Ν'-tetramethylurea hexafluorophosphate (93 mg, 0.24 mmol) and N-isopropylpropan-2-amine (49 mg, 0.48 mmol) were stirred for 5 hours. To the reaction mixture was added 1 mL of a saturated aqueous solution of sodium sulphate, and ethyl acetate (15 mL×3), and the organic phase was combined, washed with saturated sodium sulfate solution (15 mL×2), dried over anhydrous magnesium sulfate The resulting residue was purified by EtOAc EtOAc (EtOAc) eluting ,I-二曱基_异°弓丨°多琳-2-yl)Ethyl]-N-(2,3-diaminopropyl 265 95255 201242964) benzoguanamine hydrochloride 82 (31mg , white solid), yield: 26.1%. MS m/z (ESI): 558.3 [M+l] 4 NMR (400 MHz, DMSO-form, ppm): δ 9.36 (br, 1H), 8.99 (br, 1H), 8.86 (br, 1H) , 8.48 (s, 1H), 8.27 (s, 1H), 8. 12(s, 1H), 7. 45(s, 1H), 5. 54 (s, 2H), 4. 93 (s, 1H) , 4.64 (s, 1H), 4.29-4.26 (m, 2H), 4.16-4.10 (m, 2H), 3.69 (s, 1H), 3.48-3.25 (m, 4H), 1.53 (s, 6H), 1.44 -1.23 (m, 15H) Example 83 3-tert-Butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imine Base-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]benzamide hydrochloride

First step 3-tert-butyl-N-cyclopropyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1 , Γ-isoporphyrin]-2'-yl)ethinyl]benzamide hydrochloride 3-tert-butyl-5-[2-(5',6'-diethoxy-4 '-Fluoro-3'-imine 266 95255 201242964 Base-spiro [cyclopropane-1, fluorene-isoporphyrin]-2'-yl)ethinyl]benzoic acid hydrochloride 76 (51 mg, 0. lOmmol) dissolved in 2 mL of hydrazine, hydrazine-dimercaptoamine, 'addition of cyclopropylamine (llmg, 0.20 mmol), 2-(7-azobenzotriazine)-N, N, N , N,-tetradecylurea hexafluorophosphate (46 mg, 0.12 mmol) and N-isopropylpropan-2-amine (24 mg, 0.25 mmol) were stirred for 3 hours. To the reaction mixture, 10 mL of a saturated sodium chloride solution, and ethyl acetate (10 mL×3), and the organic phase was combined, washed with a saturated sodium carbonate solution (i〇mLx3), dried over anhydrous magnesium sulfate, filtered, The residue obtained was purified by EtOAc (EtOAc EtOAc) (EtOAc) -Fluoro-3,-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenylhydrazine hydrochloride 83 (48 mg, white solid) Yield: 87.3%. MS m/z (ESI): 522. 3 [M+l] lH NMR (400 MHz, DMSO-i/e, ppm): δ 9.51 (br, 1H), 9.12 (br, 1H), 8.87 (br, 1H), 8.42 (s, 1H), 8.20 (s, 1H), φ 8-〇7 (s, 1H), 7.03 (s, 1H), 5.38 (s, 2H), 4.26-4.21 (m, 2H) , 4.15-4.10 (m, 2H), 2.92-2.86 (m, 1H), 1.92-1.82 (m, 2H), 1.69-1.65 (m, 2H), 1.42-1.38 (m, 3H), 1.37 (s, 9H), 1.33-1.31 (m, 3H), 0.76-0.64 (m, 4H) Example 84 l-[3-tert-butyl-5-(morpholin-4-carbonyl)phenyl]_2_(5,, 6, _diethoxy~·4'-fluoro-3'-imino-spiro[cyclopropane_丨, Γ _isoporphyrin 2, _ keto ketone hydrochloride 267 95255 201242964

Ο 84

7β

The first step 1-[3_tert-butyl_5_(Merlin-4-yl)phenyl]_2-(5',6'-diethoxy-4'-fluoro-3'-imino - Spiro [cyclopropane-1,1'-isoindoline]-2'-ethylethanone hydrochloride 3-tert-butyl-5-[2-(5',6'-diethoxy_ 4'-Fluoro-3'-imino-spiro[cyclopropane-1,1 '-isoporphyrin]-2'-yl)ethenyl]benzoic acid hydrochloride 76 (48 mg, 0. 09mraol Dissolved in 2 mL of hydrazine, hydrazine-didecyl decylamine, added with morphine (16 mg, 0.19 mmol), 2-(7-azobenzotriazide)-N,N,Ν',Ν' - tetradecyl urea hexafluoroate (43 mg, 0.1 mmol) and N-isopropylpropan-2-amine (22 mg, 0.22 mmol), stirred for 3 hours. 10 mL of saturated sodium chloride was added to the reaction mixture. The solution was extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sulphuric acid, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography chromatography. The residue gave the title product 1-[3-tert-butyl-5-(m-lin-4-yl)phenyl]_2-(5',6'-diethoxy-4'-fluoro-3' -imino-spiro[cyclopropane-1 1'-Isoporphyrin]-2'-Ethyl Ethyl Ketone Salt 268 95255 201242964 Acidate 84 (52 rog, white solid), Yield: 96.3% MS m/z (ESI): 552.3 [M+l !H NMR (400 MHz, DMSO-i/e, ppm): δ 9.70 (br, 1H), 9.16 (br, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7. 04 (s, 1H), 5. 40 (s, 2H), 4. 24 (m, 2H), 4. 12 (m, 2H), 3.67-3.38 (m, 8H), 1.98- 1.65 (m, 4H), 1.40 (m, 3H), 1.36 (s, 9H), 1.31 (m, 3H) Example 85 Spring 3-tert-butyl-5-[2-(5,6-diethoxy) -4-4_|1~'3-Imino-1,1-dimercapto-iso-α-bendolin-2-yl)ethidyl]-N-(2-ylethylethyl)benzoquinone Amine hydrochloride

First step tert-butyl*~5-[2-(5,6-diethoxy-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl) Ethyl]-N-(2-hydroxyethyl)phenylhydrazine hydrochloride 2-Aminoethanol (I3 mg, 0.20 mmol) was dissolved in 2 mL of methane methane, and 4-diaminopyridine was added. 37 mg, 0.30 mmol), 3-tert-butyl 269 95255 201242964 -5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-didecyl-isoindole嗓琳-2-yl)ethinyl]benzoic acid hydrobromide 73 (52mg, 〇. 1〇jj) and bis(2-oxo-3-oxazolidinyl)phosphinium oxime ( 5 l mg, 〇. 20 mmol), and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 3-Imino-1,1-dimercapto-isoindol-2-yl)ethinyl]-N-(2-hydroxyethyl)benzamideamine 85 (32 mg, white solid) ), yield: 57.1%. MS m/z (ESI): 528.3 [M+l] 4 NMR (400 MHz, MSO-A, ppm): δ 9. 40 (br, 1H), 8. 98 (br, 2H), 8.54 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.46 (s, 1H), 5.58 (s, 2H), 4.91 (br, 1H), 4.27 (m, 2H), 4.14 (in, 2H ), 3.58-3.38 (m, 4H), 1.54 (s, 6H), 1.43-1.31 (m, 15H) Example 86 2-[[3-tert-butyl-5-[2-(5',6' -diethoxy-4'-oxy-3,_iminosyl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenyl]amino]acetonitrile Hydrobromide

95255 270 201242964 First step 2_[[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imido- snail [cyclopropanone- 1,1'-iso-° 引 °多琳]-2'-yl)ethinyl]phenyl]amino]acetonitrile hydrobromide 5',6'-diethoxy-7'- defeat- Spirulina [cyclopropanol-1,3'-isopopinol]-indole-imine 41g (38mg, 0.15mmol) was dissolved in 1mL of tetrahydrofuran 'add 2-[[3-(2-bromoacetamidine) 77g (45 mg, 0.15 mmol) of 5-(tert-butyl-phenyl]amino]acetonitrile, and the reaction was stirred for 2 hr. The residue obtained was purified by EtOAc EtOAc (EtOAc) elut elut elut elut elut 2-(5',6'-diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1,1'-isoindoline]-2,-yl)ethenyl Phenyl]amino]acetonitrile hydrobromide 86 (12 mg, white solid), yield: 14.6%. MS m/z (ESI): 512.6 [M+23] *H NMR (400 MHz, DMSO-i/e, ppm): δ 9.48 (br, 1H), 9.07 s (br, 1H), 7.41 (s, 1H), 7.13 (m, 2H), 7.03 (s, 1H), 6.97 (s, 1H), 6.52 (t, / = 7. 2 Hz, 1H), 5.21 (s, 2H), 4.38 (d, / =7. 2 Hz, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 1.79 (m, 2H), 1.66 (m, 2H), 1.40 (m, 3H), 1.33 (m, 12H) Example 87 3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro-3-imino-i,i-didecyl-isoindoline-2-yl) Ethyl]-N,N-bis(2-pyridylethyl)benzamide hydrochloride 95255 271 201242964

First step 3-tert-butyl-5-[2-(5, 6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl) Ethyl)-N,N-bis(2-hydroxyethyl)benzamide hydrochloride 3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro -3-imino-1,1-dimercapto-isoindol-2-yl)ethinyl]benzoic acid hydrobromide 73 (104 mg, 0.20 mmol) was dissolved in 4 mL of N,N- To methyl decylamine, 2-(2-hydroxyethylamine)ethanol (42 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N' were added. - Tetramethylurea hexafluorophosphate (93 mg, 0.24 mmol), followed by addition of N-isopropylpropan-2-amine (48 mg, 0.44 mmol). Add 20 mL of saturated sodium hydride solution to the reaction solution, extract with ethyl acetate (10 mL×3), combine the organic phase, wash the strip with saturated sodium carbonate solution (10 mL×3), dry with anhydrous sulfuric acid, filter, condense and concentrate under reduced pressure. The resulting residue was purified by EtOAc (EtOAc) elut. , 1-Dimercapto-isoindolin-2-yl)ethinyl]-N,N-bisyl)benzamide hydrochloride 87 (35 mg, white solid). Yield: 7%. </ RTI> <RTIgt; 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.46(s, 1H), 5. 49(s, 2H), 4. 94 (s, 2H), 4.27 (m, 2H), 4.13 (m, 2H), 3.66-3.51 (m, 8H), 1.51 (s, 6H), 1.41-1.23 (m, 15H) Example 88 3-tert-butyl-5-[2-(5',6' -diethoxy-4'-fluoro-3'-imino group_spiro# [cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-N-(2, 3-dihydroxypropyl)phenylhydrazine hydrochloride

First step 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-don-3'-imino-spiro[cyclopropane-1, oxime-isoindole] Phenyl]-2'-yl)ethinyl]-N-(2,3-dihydroxypropyl)phenylhydrazine hydrochloride 3-tert-butyl-5-[2-(5',6' -diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]benzoate 273 95255 201242964 The acid salt 76 (70 mg, 0.14 mmol) was dissolved in 3 mL of N,N-dimethylformamide. Add 3-aminopropanone-1,2-diol (25 mg, 0.25 mmol), 2- (7) -Azobenzotriazole)-Ν,Ν,Ν',Ν'-Tetramethylurea hexafluorophosphate (63mg, 0·16mmol) and N-isopropylpropan-2-amine (33mg, 0.32 Methyl), the reaction was stirred for 4 hours. To the reaction mixture was added 〇 〇 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 The resulting residue was purified by EtOAc EtOAc (EtOAc) elut elut Amino-spiro[cyclopropane-1,1'-isoindolyl]-2'-yl)ethenyl]-N-(2,3-dihydroxypropyl)benzamideamine hydrochloride 88 ( 45重量。 White solid), yield: 56.3%. MS m/z (ESI): 556.3 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.45 (br, 1H), 9. i〇(br, 1H), 8.79 ( Br, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.08(s, 1H), 7. 03(s, 1H), 5. 30 (s, 2H), 4. 90 (s, 1H), 4.64 (s, 1H), 4.24 (m, 2H), 4.13 (m, 2H), 3.67-3.25 (m, 5H), 1. 90 (m, 2H), 1. 65 (ra, 2H) , 1. 38 (s, 9H), 1. 31 (m, 3H), 1.23 (m, 3H) Example 89 3-tert-butyl-5-[2-(5',6'-diethoxy -4'-Fluoro-3'-imino-spiro[cyclopropane-1,1'-iso- 0-indolyl]-2'-yl)ethenyl]-N-(2-pyridyl-propyl Benzoamine hydrochloride 274 95255 201242964

First Step® 3-tert-Butyl-5-[2-(5,6,-diethoxy-4'-fluoro-3,-imino-spiro[cyclopropane-1, Γ-isoindole] Porphyrin]-2,-yl)ethenyl]-N-(2-hydroxypropyl)phenylhydrazine hydrochloride 3-tert-butyl-5-[2-(5,,6,-di Ethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1,1,-isoindoline]-2,-yl)ethenyl]benzoic acid hydrochloride 76 (70 mg , 0.14 mmol) was dissolved in 3 mL of dioxane, 4-diguanylidenepyridine (50 mg, 0.40 mmol) and 2-aminoethanol (16 mg, φ 〇. 27 mm 〇l) were added, followed by addition of bis(2- Oxo-3-oxazolidinyl)phosphinium chloride (69 mg, 〇. 27 mmol) was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Fluoro-3,imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]-^(2-hydroxypropyl)benzamine hydrochloride 89 (20 mg, white solid), yield: 26 3%. MS m/z (ESI): 526.3 [M+l] 4 NMR (400 MHz, DMSO-purin, ppm): δ 9·61 (s, 1H) 9 19 (s, 1H), 9.03 (s, 1H) , 8.58 (s, 1H), 8·33 u 1H) ', 8" 5 95255 275 201242964 (s, 1H), 7. 11 (s, 1H), 5. 49 (s, 2H), 4. 97 ( s, 1H), 4. 31 (m, 2H), 4. 20 (m, 2H), 3.63 (m, 2H), 3. 40 (in, 2H), 1.93 (s, 2H), 1.73 (s, 2H), 1.44 (m, 15H) Example 90 l-[3-tert-butyl-5-(2-carbylethoxy)phenyl] 2-(5',6,diethoxy- 4'-Fluoro-3'-imino-spiro[cyclopropane-1,1,-isoindoline]_2, _yl) ethyl ketone hydrobromide

The first step 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone will be cuprous iodide (573 mg, 3 mmol), L-proline (690 mg, 6 mmol) and carbonic acid铯 (19. 56 g, 60 mmol) was added to the reaction flask, and 5 mL of 1-(3-indol-5-tert-butyl-phenyl)ethanone 77d (2.55 g, 10 mmol) of bismuth sulfite was added. Wind was added to the reaction system, and ethylene glycol (15 mL, 305 mmol) was added thereto, and the reaction was stirred for 12 hours. The reaction solution was poured into 5 mL of a saturated ammonium sulfate solution, and 20 mL of ethyl acetate and 20 mL of water were added thereto, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL), and the organic phase was combined with water (20 mL×2) and saturated sodium carbonate. The solution was washed (30 mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford 276 95255 201242964 title product [3-tert-butyl-5 -(2-Phenylethoxy)phenyl]ethanone 9A (198 mg, brown oil). Second step 2-bromo-l-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone 1-[3-tert-butyl-5-(2-hydroxyethoxy) Phenyl]ethanone 9〇a (198 mg, 〇. 84 mmol) was dissolved in 7 mL of tetrahydrofurfuran and decyl alcohol (v/v = 6:i) in a mixed solvent, and tridecylphenylammonium tribromide ( 4 〇 4 mg, 〇 84 mm 〇 1), and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified residue purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted 9%。 Ethyl ketone 9 〇 b (19 〇 mg, yellow oil), yield: 71.9%. Third step H3-tert-butyl-5-(2-hydroxyethoxy)phenyl]_2_(5',6,-diethoxy-4-fluoro-3'-imino-spiro[cyclopropane烧_1,1,_异吲哚琳]_2' _ base) ethyl ketone hydrobromide φ 5,6 _diethoxy-7'-fluoro-spiro [cyclopropane-1,3,- Isoporphyrin]-indole-imine 41g (85mg, 〇.32mmol) was dissolved in 2mL of tetrahydrofuran, added 2-bromo-1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl Ethylketone 90b (100 mg, 0.32 mmol) was stirred for 12 hours. Filtration gave a white solid, which was washed with EtOAc EtOAc (EtOAcjjjjjjjj 5,6,6 Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane_丨, 丨, _isoindole]-2-yl)ethanone hydrobromide 9 〇 (42 mg, white solid), yield: 22.9%. </ RTI> <RTIgt; ), 7.40 (s, 1H), 7.3 〇 (: s, 1H)' 7. 〇 4 (s, 1H), 5.23 (s, 2H), 4.93 (t, / = 5.2 hz, ih) 4 25 (m , 2H), 4.12 (m, 2H), 3_ 77 (m, 2H), 3.40 (m, 2jj) 丨 8 〇 (m, 2H), 1.67 (m, 2H), 1.41 (m, 3H), l 33 (s, 9H)j (m, 3H) Example 91 1-(3-tert-butyl-5-methyl-bromo-phenyl)_2-(5,6-diethoxy_4_gas-3 -imino-1,1-dimethyl-iso,dolyl-2~yl)ethanone hydrobromide

The first step is 1-(3-tert-butyl-5-methyl-bromo-phenyl) ethyl ketone 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (1.53 g, 6 mmol ), a succinyl sodium (2.45 g, 24 mmol) and trifluoromethyl copper (i) benzene (300 mg, 0.40 mmol) were dissolved in 40 mL of dimethyl hydrazine, and Ν, Ν' - 5小时。 The reaction was stirred for 2.5 hours at 150 ° C. Pour 50 mL of water and 50 mL of ethyl acetate into the reaction mixture, and extract the mixture. The aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phase was combined and washed with water (30mL×3) 278 95255 201242964 and saturated sodium chloride solution (30 inLx3) The 'anhydrous sulphuric acid was dried and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc -Phenyl) Ethyl ketone 91a (1.16 g, yellow liquid), Yield: 76.1%. Step 2 2-Bromo-1-(3-tert-butyl-5-nonylsulfonyl-phenyl)ethanone 1-(3-tert-butyl-5-methylsulfonyl-phenyl)ethanone 91a (200 mg, 0. 79 mmol) was dissolved in 20 mL of tetrahydrofuran, and tridecylphenyl tri-ammonium (296 mg, 0.79 mmol) was added, and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 911) (21 〇 1 ^, pale yellow liquid), yield: 80.2%. MS m/z (ESI): 350.0 [M+18] Step 3 1-(3-tert-butyl-5-methylsulfonyl-phenyl)-2-(5,6-diethoxy-4 -Fluoro-3-imino-1,I-indolyl-iso-bendo-oxo-2-yl)ethanone hydrochloride salt 5,6-diethoxy-7-fluoro-3 , 3-dimercapto-isoindole-p-amine 24d (79mg, 0.30mmol) was dissolved in uomL tetrahydrofuran, and 2-bromo-1-(3-tert-butyl-5-nonylsulfonyl-phenyl) was added. Ethyl ketone 91b (l 〇〇 mg, 0. 30 〇 1) was scrambled for 14 hours. The reaction mixture was concentrated under reduced pressure, and then purified by EtOAc EtOAc (EtOAc). Washing, vacuum drying, to give the title product 1 gas ^ 丁 美 美 5 一 一 一 - - - - - - ( ( ( ( ( ( ( ( ( ( ( ( ( 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 95 Di-mercapto-isoindolino-2-yl)ethanone hydrobromide 91 (30 mg, white solid), yield: 16.8%. MS m/z (ESI): 519. ] R (400 MHz, DMSO-忒, ppm): δ 9.42 (br, 1H), 9.02 (br, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.46(s, 1H), 5.58(s, 2H), 4. 26 (m, 2H), 4. 12 (m, 2H), 3.36 (s, 3H), 1.53 (s, 6H), 1.41 (m, 12H), 1.30 (m, 3H) Example 92 φ 1-(3-tert-butyl-5-methylglycine-phenyl)-2-(5',6'-diethoxy_4' -1_3' -imino-spiro[cyclopropane-1, Γ-iso-α-引 π 吓 ·]-2'-yl) ethyl ketone oxime bromide

First step 1-(3_tert-butyl_5_曱 酿 --phenyl)-2-(5',6' _diethoxy_4'-fluoro-3'-imido- snail [cyclopropane-1, hydrazine-isoporphyrin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxy-7'-don-snail [cyclopropane-1, 3'-Different 〇 280 95255 201242964 ]]-Γ-imine 41g (79mg, 0. 30mmol) dissolved in 2mL tetrahydrofuran South 'Add 2-'; odor-1-(3-tertidine Base-5 - hydrazine-phenyl)ethanone 9ib (100 mg, 0.30 mmol) was stirred for 2 hr. Filtration, washing with tetrahydrofuran (0.5 mL×2), and dried in vacuo to give the title product 1-(3-tert-butyl-5-methylmercapto-phenyl)-2-(5',6'-diethoxy _4'-Fluoro-3'-imino-spiro[cyclopropane-1, Γ-iso. 引 D朵琳] - 2, _yl) ethyl ketone hydrobromide 92 (85 mg, white solid), Yield: 47. 5%. MS m/z (ESI): 517.2 [M+l] Φ.H NMR (400 MHz, DMSO-i/e, ppm): δ 9.42 (br, 1H), 9.12 (br, 1H), 8.33 (s, 1H), 8.24 (m, 2H), 7.04 (s, 1H), 5. 34(s, 2H), 4. 23(m, 2H), 4. 12 (m, 2H), 3. 34 (s, 3H), 1.88 (m, 2H), 1.67 (m, 2H), 1.40 (m, i2H), 1.29 (m, 3H) Example 93

L-[3-tert-Butyl-5-(2,3-dihydroxypropoxy)phenyl]_2_(5,6, bis-diethoxy-4'-fluoro-3'-imino- Spirulina [cyclopropane_丨, 丨, _ iso- 吲哚]-2'-yl) acetamidine hydrobromide

First step 95255 281 201242964 1-[3~tert-butyl-5-(2,dihydroxypropoxy)phenyl]ethanone will be cuprous iodide (153rog,0·8〇_〇1), L- Choline acid (184 mg, 1.60 mmol) and saponin (5.2 g, i6 mmol) were added to the reaction flask, and 3 mL of 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (1) was added. 〇2g, 4mm〇1) of Ν, Ν-dimethyl ketoamine solution and 27mL of glycerol (ng, 〇 12mol) of N'N-dimethylformamide solution, 9〇&lt;&gt;c The reaction was stirred for 48 hours. After cooling to room temperature, the reaction mixture was quenched by adding 1 mL of saturated ammonium sulfate solution, 20 mL of ethyl acetate and 2 Torr of water were added, and the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (2 mL) The organic phase was combined, washed with water (3 〇 mL) and saturated sodium chloride solution (3 〇mL×2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified to give the title product: 1-[3-tert-butyl-5-(2,3-dihydroxypropyloxy)phenyl]ethanone 93a (289 mg, brown liquid). . Second step 2-bromo-l-[3-tert-butyl-5-(2,3-dihydroxypropoxy)phenyl]ethanone Copper bromide (103 mg, 0.46 mmol) was suspended in 1.50 mL of ethyl acetate The ester was heated to reflux, and 2.50 mL of 1-[3-tert-butyl-5-(2,3-di-propylpropoxy)phenyl]ethanone 93a (61 mg, 0·23 mmol) of trichlorobenzene was added. The solution was shaken and refluxed for 3 hours. After cooling to room temperature, filtration and concentrating the filtrate under reduced pressure afforded crude title product 2-bromo-1-[3-tert-butyl-5-(2,3-dipropylpropoxy)phenyl]ethanone 93b ( 105 mg, dark brown oil), the product was taken to the next step without purification. The third step is 1-[3-tert-butyl-5-(2,3-di-propylpropoxy)phenyl]-2-(5',6'-di-282 95255 201242964 ethoxy-4'-fluoro -3,-imino-spiro[cyclopropane-i,1,-isoporphyrin]-2'-yl)ethanone hydrobromide salt 5',6'-diethoxy-7'- Fluoro-spiro[cyclopropane-1,3'-isoindole]-1 -imine 41g (84mg, 0.30mmol) and crude 2-bromo-l-[3-tert-butyl 5 (2, 3- The propyloxy)phenyl]acetamidine 93b (105 mg, 0·30 〇1) was dissolved in 150 mL of tetrahydrofuran, and the reaction was stirred for 4 hours to precipitate a large amount of solid. Filtration, the filter cake was washed with EtOAc (2 mL EtOAc) (EtOAcjjjjjjj ,6,-Diethoxy-4'-fluoro-3,-imino-spiro[indane-1, hydrazine-isoindoline]-2, yl) ethyl ketone hydrobromide 93 ( 38 rag, white solid), Yield: 23.7%. MS m/z (ESI): 529.7 [M+l], NMR, NMR, DMSO, mp. , 1H), 7.30 (s, 1H), 7' 〇 3 (s, 1H) 5.21 (s, 2H), 4.98 (m, 1H), 4.71 (m, lH), 4 23 (m 2H) φ 4.11 ( m, 3H), 3.97 (ffi, 1H), 3.82 (m, 1H), 3 6〇 (m: i team 1.80 (m, 2H), 1.66 (m, 2H), 1·40〇η, 3H), l 33 (m 12H) Example 94 3-tert-Butyl-5-[2-(5,6-diethoxy-4-fluoro~3~imino)-^-dimethyl-iso-bow Budolin-2-yl)ethyl benzoate

95255 283 201242964

Step 3 3-Ethyl _5-tert-butyl-benzoquinone 1-(3-indol-5-tert-butyl-benyl)-B-77d (lg, 3.92 mmol) and copper cyanide ( 386 mg, 4.31 mmol) was dissolved in 15 mL of N-mercapto-2-σ ratio 11 alkanone, and the reaction was stirred at 170 ° C for 2 hours. 2 mL of ethyl acetate and 20 mL of water were added to the reaction solution, and then 1 mL of aqueous ammonia was added thereto, and the mixture was stirred for 3 minutes, and the organic phase was extracted and extracted with ethyl acetate (10 mL mL), and the organic phases were combined. It was washed with water (15 mL×3) and a saturated sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give the title product. Ethyl ketone _5_tert-butyl-benzonitrile 94a (480 mg, yellow solid), yield: 6 9%. MS m/z (ESI): 219.1 [M+18] Step 2 3-(2-bromoethylidene-tert-butyl-benzofuronitrile) 3-Ethyl-5-tert-butyl, phenyl 94a (3 〇〇 mg, 1 49 〇 〇 1) was dissolved in 15 mL of tetrahydrofuran, added tridecyl phenyl three desertification (561, 1.49_1), and the reaction was stirred for 3 。 minutes. Filtration, filtrate The organic layer was concentrated under reduced pressure, and the obtained residue was obtained from the crystals of (4) to give the title product 3-(2-bromoethyl)-5-tert-butyl-benzoic acid nitrile 94b (345 mg, yellow liquid). , Yield: 82. 5% » ' 95255 284 201242964 MS m/z (ESI): 299.0 [M+18] Step 3 3-tert-butyl-5-[2-(5, 6-diethoxy) 4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethenyl]benzonitrile hydrobromide 5,6-diethoxy-7 -Fluoro-3,3-dimethyl-isoindol-1-amine 24d (95 mg, 〇. 36 mmol) was dissolved in 1.5 mL of tetrahydrofuran, and 3-(2-bromoethyl)-5-tert-butyl was added. Ben-benzonitrile 94b (100mg, 〇. 36mmol), stir

Mix and react for 12 hours. Directly prepared, a yellow solid was obtained, 15 mL of ruthenium tetrahydrofuran was added, and the mixture was stirred for 10 minutes, and the solid was obtained by trituration, and washed with four broth (5 mL×3). —[2_(5,6-diethoxy-4-fluoro-3-iminobisdidecyl-isoindoline-2-yl)ethenyl]benzoquinone hydrobromide 94 (35 mg, White solid), Yield: 17.9%. MS m/z (ESI): 466.3 [M+l] H NMR (400 MHz, DMS0-af6, ppm): δ 9.44 (br, 1H), 9.05 ( (br, 1H), 8.45 (s, 1H), 8.25 (m, 2H), 7.46 (s, 1H), 5. 52 (s, 2H), 4. 26 (m, 2H), 4. 11 (m, 2H), 1. 51 (s, 6H), 1.43 (m, 3H), 1.37 (s, 9H), 1.31 (m, 3H) Example 95 3-tert-butyl-5-[2-(5',6,-diethoxy-4,-fluoro _3, _imino-spiro[裱propane-1, Γ-isoporphyrin; |_2' _yl) ethenyl] benzoquinone hydrobromide 285 95255 201242964

First step 3-tert-butyl-5-[2-(5',6'-diethoxy-4,-fluoro-3'-imino-spiro[cyclopropane-1, oxime-isoindole] Porphyrin]-2, _yl)ethylidene]benzoquinone hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane_丨,3, _isoporphyrin ]-1'-imine 41g (94mg, 0.36mmol) was dissolved in i.5mL tetrahydrofuran, and 3-(2-bromoethenyl)-5-tert-butyl-benzonitrile 94b (1〇〇mg, 0.36_〇1), the reaction was stirred for 12 hours. The solid was filtered, washed with THF (0.5 mL×2) and dried in vacuo to give the title product: 3-tert-butyl_5_[2-(5',6'-diethoxy-4'-fluoro-3'-imine (1), a yield of 51. 5%. A sulfonate [cyclopropanol-L κ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ MS m/z (ESI): 464.2 [M+l], NMR (400 MHz, DMSO-^, ρριη): δ g (br, 1H), 8.35 (s, 1H), 8.26 (s, 7 . 04 (s, 1H), 5. 27 (s, 2H), 4. 23 (m 1. 77 (m, 2H), 1. 66 (m, 2H), l. 4i (m 1.31 (m, 3H) • 40 (br, 1H), 9. li 1H), 8.20 (s, 1H), 2H), 4. 10 (m, 2H), 3H), 1.36 (s, 9H), 95255 286 201242964 Example 96 1-[3-tert-butyl-5-(hydroxyindenyl)phenyl]- 2-(5',6,-diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-I _ _ ° 弓 卜 朵 朵 ] ] ] ] ] ] ] ]

The first step of 1-(3-bromo-5-tert-butyl-phenyl)furfural 1,3-dibromo-5-tert-butyl-benzene 77c (17 S, 58.40 mmol) was dissolved in 120 mL of tetrahydrofuran. n-Butyllithium (23. 4 mL, 58.40_〇1) was added dropwise at -78 ° C, and the reaction was stirred for 0.5 hour. Further, N,N-dimercaptoguanamine (6. 40 g, 87.70 mmol) was added, and the reaction was stirred for 5 hours. To the reaction mixture, a solution of 12 mL of saturated ammonium sulfate was added, and ethyl acetate was extracted (50 mL×2). The organic phase was combined, washed with saturated sodium carbonate solution (3 〇mL×3), dried over anhydrous magnesium sulfate Concentration, the residue was purified by EtOAc EtOAc EtOAc (EtOAc) : 80.0%. The second step (3 genus-5~tert-butyl-phenyl) decyl alcohol 287 95255 201242964 1-(3-Bromo-5-tert-butyl-phenyl)ethanone 96ad. 2〇g, 4.98mm〇 l) Dissolved in 16 mL of absolute ethanol, sodium borohydride (57 mg, ljginmol) was added in portions, and the reaction was stirred for 45 minutes. The reaction mixture was quenched with water (20 mL). Filtration and concentrating the filtrate under reduced pressure afforded the title product (3-bromo-5-tert-butyl-phenyl) decyl alcohol 96b (g, white solid). The third step 1-[3-tert-butyl-5-(hydroxymethyl) phenyl] ethyl ketone (3-di-5-tert-butyl-phenyl) decyl alcohol 96b (79 〇 mg, 3 25 mm 〇 l) Dissolved in 15 mL of tetrahydrofuran at _78. Add n-butyl lithium (5 2 〇 mL, 13 〇 1), stir the reaction for 30 minutes, and then add N,N-dimercaptoacetamide (850 mg, 9.75 〇1), and stir the reaction. 3 minutes. 60 mL of saturated ammonium hydride solution was added to the reaction mixture, and the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phase was combined and washed with saturated sodium chloride solution (60 mL) and dried over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with EtOAc EtOAc (EtOAc) : (n4 mg, colorless liquid), Yield: 17.0% MS m/z (ESI): 207.1 [M+l] Step 4 2-bromo-l-[3-tert-butyl-5-(hydroxymethyl) Phenyl]ethanone 1-[3_tert-butyl-5-(hydroxyindenyl)phenyl]ethanone 96c (1〇7mg, 0·52, 1〇1) was dissolved in 3mL of tetrahydrofuran Methylphenyl tri-amylation 95255 288 201242964 Ammonium (195 mg, 0.52 min), stirred for 1 hour. Filtration and concentration of the filtrate under reduced pressure 'purification of the residue obtained by thin-layer chromatography chromatography to afford 2-bromo-l-[3-tert-butyl-5-(hydroxyindenyl)phenyl]ethanone 96d (90 mg, mp. [M+l] The fifth step l-[3-tert-butyl-5-(hydroxyindenyl)benzene A 2-(5,6,-diethoxy-4-disorgano-3-imino-spiro[cyclopropyl--,ι' _ 异 卜 淋 ]]_2, _ base) ???S and hydrogen oxalate salt 5,6'-diethoxy-7'-fluoro-spiro[cyclopropanone_1,3,-isoporphyrin]-indole-imine 41g (73mg, 0.28mmol Dissolved in 2 tetrahydrofuran, 2-bromo-l-[3-tert-butyl-5-(hydroxyindenyl)phenyl]ethanone 96d (87 mg, 0.30 mmol), and stirred for 2.5 hr. Washed with tetrahydrofuran (0.5 mL×2) and dried in vacuo to give the title product s-tert-butyl-5-(ylmethyl)phenyl]-2-(5',6'-diethoxy a 4, fluoro--3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2, yl)ethanone hydrobromide 96 (55 mg, white solid), Rate: 34.3% MS m/z (ESI): 469.3 [M+l] ^ MR (400 MHz, DMSO-' ppm): δ 9.42 (br, 1H), 9 16 (br, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 5.24 (s, 2H), 4.60 (s, 2H), 4.26-4 21 (m, 2H) , 4.15-4.10 (m, 2H), 1.86-1.78 (m, 2H), 1.69- 1.63 (m, 2H), 1.42-1.38 (m, 3H), 1.34 (s, 9H), i.32- 1.29 ( m, 3H) 95255 2 89 201242964 Example 97 l-[3-tert-Butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino- 1,1-didecyl-isoindoline-2-yl)ethanone hydrogen-filled acid

First step 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]_2-(5,6-diethoxy-4-fluoro-3-imino-1,1 -Dimethyl-isoindoline-2-yl)ethanone hydrobromide 5' 6-diethoxy-7-fluoro-3,3-dimethyl-isoindole-1-amine 24d ( 76 mg, 0.29 mmol) was dissolved in 2 mL of tetrahydrofuran and added 2-; odor-1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone 9 〇b (9 〇 mg, 0) 29 〇 1), stirring reaction for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjj , 6-diethylindolyl-4-fluoro-3-imino-1,1-dimercapto-isoindoline-2-yl)ethanone hydrobromide 97 (33 mg, pale yellow solid), Yield: 23.1〇/. </ RTI> </ RTI> <RTIgt; 1H), 7.44 (s, 2H), 7.30 (s, ih), 5. 41 (s, 2H), 4. 60 (s, 2H), 4. 26 (m, 2H), 4. 12 (m, 4H), 3.76 (in, 2H), 1·51 (s, 6H), 1.42 (m, 3H), 1.34 (m, 12H) Example 98 l-[3-tert-butyl-5-(hydroxy fluorenyl) Phenyl]- 2-(5,6-diethoxy-oxy-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide

First step 1-[3-tert-butyl-5-(hydroxyindenyl)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1,1-di曱-iso-β ° 朵 -2- 基 基 基 乙 乙 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 24d (90mg, 0.34mmol) was dissolved in 3mL of tetrahydrofuran, and added 2-bromo-l-[3-tert-butyl-5-(pyridinyl)phenyl]ethanone 96d (116mg,0 · 41 mmol), the reaction was stirred for 16 hours. The residue was purified under reduced pressure. 5,6-diethoxy-4-fluoro-3-ya 291 95255 201242964 Amino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide 98 (3〇mg , white solid), yield: 16.1%. MS ra/z (ESI): 471.1 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.42 (br, 1H) 9 〇〇 (br, 1H), 7.90-7.88 (m) , 2H), 7.72 (s, 1H), 7 46 (s 1H), 5.47-5.44 (in, 2H), 4.61-4.60 (m, 2H), 4.29-4 24 (m, 2H), 4. 15- 4· 10 (m, 2H), 1· 53 (s, 3H), l· 5i (s 3H) 1.43-1.39 (in, 3H), 1.35 (s, 9H), 1.32-1· 3〇 (m 3H Example 99 l-[3-tert-Butyl-5-(1-methyl 0-O-p--4-yl)phenyl]_2-(5 6-diethoxy-4-fluoro-3-A) Amino-1,1-dimethyl-isoindolyl) ethyl ketone hydrobromide

First step 1-[3-tert-butyl-5-(1-mercaptopyrazole-4-yl)phenyl]ethanone 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (72〇mg, 2. 83 〇1) and four (two basal scales (327mg, 〇. 28πππο1) were dissolved in 50mL of dimethyl ether, stirred for 1 minute, and then added 7mL of 1-methylpyrazine 292 95255 201242964 An aqueous solution of saliva-4-ylboronic acid (533 mg, 4.23 mmol) and potassium carbonate (1.95 g, 14.10 mmol) was heated to reflux and stirred for 4 hours. filtered, 20 mL ethyl acetate was added to the filtrate, and extracted. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by eluent column chromatography with eluent column chromatography to give the title product 1-[3-s-butyl-5-(1-methylindole ratio Oxazol-4-yl)phenyl]ethanone 99a (318 mg, pale yellow oil), yield: 44. 0%. MS m/z (ESI): 257.1 [M+l] 1-l-[3-tert-butyl-5-(1-indolylpyrazole-4-yl)phenyl]ethanone 1-[3-tert-butyl-5-(1-indenyl-n-pyrene-pyrene- 4-yl)phenyl]ethanone 99a (3〇〇mg' l.i7mm〇i) was dissolved in 5 mL of trichloromethane, and copper bromide (522 mg, 2.34 mmol) was added to raise the temperature to 4 (TC stirring reaction 12 hour After the transition, the filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford the title product 2-bromo-1 -[3-tert-butyl-5-(1 - fluorenyl π ratio Azolyl)phenyl]ethanone 99b (216 mg, light yellow oil), yield: 55.0%. Step 3 1-[3-tert-butyl-5-(diphenylpyrazole-4-yl) Phenyl]_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindolin-2-yl)ethanone hydrobromide salt 5, 6-Diethoxy-7-fluoro-3,3-dimercapto-isoindol-1-amine 24d (4 〇 mg, 〇.i5 mmol) was dissolved in imL tetrahydrofuran, and 2-bromo-1 was added. 3-tert-Butyl-5-(b-methylpyrazole-4-yl)phenyl]ethanone 99b (51 mg, 293 95255 201242964 0. 15 mmol), stirred for 12 hrs, filtered to give a solid, washed with tetrahydrofuran (0.5 mL×2) Drying in vacuo gave the title product 1-[3-tert-butyl-5-(1-methyloxazol-4-yl)phenyl]-2-(5,6-diethoxy-4-fluoro- 3-Imino-1,1-dimercapto-isoindolin-2-yl)ethanone argonate 99 (40 mg, white solid), yield: 44.0% MS m/z ( ESI): 521.3 [M+l] 4 NMR (400 MHz, DMSO-form, ppm): δ 9. 33 (br,1H), 8.95 (br, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7. 95(s, 1H), 7. 83(s, 1H), 7.46(s, 1H), 5. 46 (s, 2H), 4.30-4.25 (m, 2H), 4.17-4.11 (m, 2H), 3.91 (s, 3H), 1.53 (s, 6H) , 1.43 (m, 3H), 1.39 (s, 9H), 1.32 (m, 3H) Example 100 l-[3-tert-butyl-5-(1-indolylpyrazol-4-yl)phenyl] -2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone Hydrobromide

First step 294 95255 201242964 l-[3-tert-Butyl-5-(1-indolylpyrazol-4-yl)phenyl]- 2-(5,6, _diethoxy_4' - Fluoro-3'-imino-spiro[cyclopropane-1,1' _iso. 丨 n nlin]_2, yl) ethyl ketone hydrobromide 5,6 _-ethoxy-7 -Fluoro-spiro[cyclopropane_ι,3,~iso,π朵淋] -1'-imine 41g (51mg, 0.19mmol) was dissolved in 〇. 5mL tetrahydrofuran, adding 2-bromo-1-[ 3-tert-Butyl-5-(1-indolylpyrazol-4-yl)phenyl]ethyl-99b (65 mg, 0·19 mmol). The reaction mixture was concentrated to give a white solid crystals, which was crystallised from EtOAc EtOAc (EtOAc) ',6'-Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropyl y, _ 吲 吲 ° Du Lin]-2'-yl) ethyl ketone hydrobromide 1 %(1 img, white solid), yield: 10. 0%. MS m/z (ESI): 519.1 [M+l] 4 NMR (400 MHz, DMSO-' ppm): δ 9.59 (br, 1H) 9 i3 (br, 1H), 8.37 (s, 1H), 8.07 ( s, 1H), 8.05 (s, ' ll 〇 7. 7. 94 (s, 1H), 7. 79 (s, 1H), 7. 05 (s, 1H), 5. 37 (s', 2H)' 4.27-4. 22 (m, 2H), 4.16-4. 11 (m, 2H), 3.90 (s, 3H)' 1· 78 (m, 2H), 1. 68 (m, 2H), 1.41 (m , 3H), 1. 38 (s 9H)' 1.32 (m, 3H) ' ' Example 101 1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5, 6-di Ethoxy~4, gas-3 imino-1,1-dimercapto-isoindol-2-yl) ethyl ketone hydrogen acid step 95255 295 201242964

Step 1 - Molyl-3-tert-butyl-5-isopropyl-benzene. Dissolve zinc hydride (3.66 g, 26.70 mmol) in 20 mL of tetrahydrofuran. Add 2 M isopropylmagnesium hydride 13 3 mL, 5 (TC stirred for 3 hours. Add L 3-dibromo-tert-butyl-benzene 77c (5. 20 g, Π. 80 mmol) to another reaction flask, and add cuprous iodide (203 mg, 1. 07mmol), 1, 1, and - (one 卞 base disc) fluorodipentane iron (651mg, 0.89 〇1) and 2〇niL tetrahydrofuran, dripping into the cooled reaction solution, stirring reaction in the dark 36 After filtration, the filter cake was washed with ethyl acetate (2 mL mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B. The title product, bromo-3-tert-butylisopropyl-benzene 101a (433 mg, yellow oil) was obtained, yield: 95.0 〇 / 〇. Step 2 1-(3-tert-butyl-5-isopropyl 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Butyl lithium (1.37mL, 3.44mm〇l), stir the reaction for 2 hours, then drip N, N_ 95255 296 201242964 Dimercaptoacetamide (0.37 mL, 4.29_〇1), the reaction was stirred for 3 minutes, and the reaction solution was added with 20 mL of saturated ammonium chloride solution to quench the reaction. Add 5mL of water and 20mL of acetic acid to extract the organic phase, extract the organic phase with saturated sodium hydride solution (5mL), dry with anhydrous magnesium sulfate, transfer, the filtrate is concentrated under reduced pressure, using the gel column chromatography to eluent The obtained residue was purified to give the title compound 1-(3-tert-butyl-5-isopropyl-phenyl)ethyl- i </RTI> </ RTI> </ RTI> (379 mg, colorless liquid). (ESI): 219.1 [M+l] 3rd step 2-bromo-1-(3-tert-butyl-5-isopropyl-phenyl)acetamidine 1-(3-tert-butyl-5- Isopropyl-phenyl)ethanone l lb (326 mg, 1.50 mmol) was dissolved in 3 mL of tetrahydrofuran 'Addition of tridecylphenylammonium bromide (562 mg, 1.50 nmiol) 'Stirring reaction for 1 hour. Filtration, The filtrate was concentrated under reduced pressure, and the residue obtained was purified from silica gel column chromatography to afford the title product 2-bromo-1-(3-tert-butyl-5-isopropyl-phenyl)ethyl </RTI> 〇 lc (207 mg, colorless liquid), yield: 46.0% MS m/z (ESI): 299.9 [M+l] Step 4 1-(3_tert-butyl-5-isopropyl-phenyl)-2-(5,6-diethoxy-4- Gas-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3, 3-di Indole-isoindole-1-amine 24d (49 mg, 0.18 mmol) was dissolved in 〇. 5 mL of tetrahydrofuran 'Addition of 2-bromo-indole-tert-butyl-5-isopropyl-phenyl) Ethyl ketone Ic (55 mg, 〇. 18 mmol) was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc EtOAc EtOAc. 5,6-Diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide ιοί (2〇mg, white solid ), yield: 19.0%. MS m/z (ESI): 483. 5 [M+l] !H NMR (400 MHz, dUSO-ώ, ppm): δ 7.86 (s, 1H), 7 77 (s, 1H), 7.65 (s, 1H), 7.44 (s, 1H), 5.40 (s, 2H), 4.27-4.26 (m, 2H), 4.16-4.11 (m, 2H), 3.04 (m, 1H) 1.52 (s, 6H), 1.43 ( m, 3H), 1.36 (s, 9H), 1.34-1.27 (m, 9H) Example 102 1-(3-tert-butyl-5-isopropyl-phenyl)-2-(5',6' -diethoxy- 4' __良-3'-imino-spiro[cyclopropane-1,1 isoporphyrin]-2,-yl)ethanone hydrochloride

The first step is 1-(3-tert-butyl-5, isopropyl-phenyl)_2_(5',6, _diethoxy-4, fluoro]'-imino-epicyclopropene卜异+朵淋^^乙纲土土95255 298 201242964 acid salt 5,6 - ethoxy _ 乱-螺[环丙烧- i,3'-iso σ 〇 〇 〇 ] ] -1 -1 -1 Imino 41g (50mg, 0.19mmol) was dissolved in 5.5mL tetrahydrofuran 'Add 2-bromo-1-( 3-tert-butyl-5-isopropyl-phenyl)ethanone iqic (56mg,0. 19丽〇1), the reaction was stirred for 12 hours. The title compound was obtained eluted with EtOAc EtOAc (EtOAc) ',6'-Diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethanone hydrobromide 102 (30 mg, mp. 1H), 9 〇β (br, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.04 (s, 1H), 5.23 (s, 2H), 4.27-4.22 (m, 2H), ' 4. 16-4. 11 (m, 2H), 3.04-2.99 (m, 1H), 1.83 (m, 2H), 1.67 (m, 2H), 1.41 (m, 3H), 1.35 ( s, 9H), 1. 32 (m, 3H)! φ 1.25 (d, / = 9.3 Hz, 1H) ' Example 103 1_[ 3-tert-butyl-5-[4-(2-ylethyl) ) 嗓__i_基]Phenyl]-1-2 (5,6-diethoxy-4-fluoro-3'-imino-spiro[cyclopropyl]_ι,ι,_异°#朵琳]-2'-yl) acetamidine hydrochloride 5.5255 299 201242964

The first step is 1-dimethyl-3-tert-butyl-5-(1,i-dimethoxyethyl)benzene-b (3-di-5-tert-butyl-phenyl)ethanone 77d (2. 3 〇 g, 9 mm 〇 1) Dissolved in 3 mL of methanol, and then added trimethoxymethane (2.98 g, 27 mm 〇1) and camphorsulfonic acid (105 mg, 0.45 mm 〇l), and allowed to react for 12 hours. Add 500mg of potassium carbonate to the reaction solution, stir for 1 minute, add 1 〇乩 water and 10mL Zhengjiyuan 'extraction liquid, extract the aqueous phase with n-hexane (1〇mLx2), combine the organic phase, and saturate the sodium carbonate solution. Wash (1 〇 mL), dry over anhydrous magnesium sulfate <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (2 7 〇g, pale yellow oil) 'The product was taken directly to the next reaction without purification. The second step 1-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]piperazine will be the crude 1-bromo-3-tert-butyl-5~(1, Methoxyethyl)benzene 1〇3a (2.70 g, 9 mmol) was placed in a reaction flask, followed by 2-dicyclohexylphosphorus 300 95255 201242964

-2-(N' N-dimethylamino)biphenyl (i77 mg, 〇. 45 mmol), tris(diphenylidene propyl) dipalladium (270 mg, 10%), sodium tert-butoxide (2.60 g, 27 mmol) and 0-azine (1.50 g, 18 mmol), finally added 40 mL of dioxane, and stirred at 60 ° C for 3 hours. To the reaction mixture, 5 mL of water and 20 mL of ethyl acetate were added, and the aqueous phase was extracted with ethyl acetate (2 mL mL 4), and the organic phase was combined and washed with saturated sodium chloride solution (3 mL mL), anhydrous magnesium sulfate Drying, filtration, and EtOAcqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The product was directly subjected to the next reaction without purification. The third step is 1-(3-tert-butyl-5-birazoline-1-yl-phenyl)ethanone. The crude 1-[3-tert-butyl-5-(1,1-dimethoxyethyl) Phenyl] ruthenium 103b (2 g, 6.50 mmol) was dissolved in 30 mL of 2M hydrogen chloride dioxane solution, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc m.) To the crude title product 1 -(3-tert-butyl-5-br.-l-yl-phenyl)-ethyl-l-cc (1. MS m/z (ESI): 261.1 [M+l] Step 4 l-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazine-i-yl]phenyl]ethanone The crude 1-(3-tert-butyl-5-piperazin-1-yl-phenyl)ethanone i〇3c (1.40 g, 5.38 mmol) was dissolved in i 〇 mL N,N-dimercaptocarboxamide In the amine, 301 95255 201242964 Further, 2-chloroethanol (694 mg, 8.60 mniol) and potassium carbonate (1.48 g, 10.76 mmol) were added, and the mixture was heated to 7 ° C and stirred for 12 hours. 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×4), and the organic phase was combined, washed with saturated sodium sulfate solution (5 〇mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained by purifying the eluent system A was added to the title product 1-[3_tert-butyl-5-[4-(2-pyridylethyl)0 bottom -1--l-yl]]] B g with l 3d (630 mg, yellow oil), yield: 39.3%. MS m/z (ESI): 305.1 [M+l] Step 5 2-&gt;Smell-l-[3-tert-butyl-5-[4-(2-ylethyl) Phenyl] Ethyl Ketone 1-[3-tert-Butyl-5-[4-(2-hydroxyethyl)piperazinyl]pyridyl] Ethyl Ketone 103d (10 mg, 0.34 mmol) was dissolved in 2 mL of ice To the acid, add tribromopyridinium salt (10 mg, 0.34 mmol), and add 5 raL of water to the reaction mixture for 5 hours. Adjust pH 7 with sodium bicarbonate to extract with ethyl acetate (10 mL X4). The organic phase was combined, and the saturated gasified sodium solution was washed (10 mL), filtered under anhydrous acid-drying, and the filtrate was concentrated under reduced pressure. The residue was purified by eluent column chromatography with eluent system A. Bromo+[3-tert-butyl+[4-(2-hydroxyethyl)piperidine: ":Phenyl]ethanone 103e (38 mg, white solid), yield: violent 2/, violent" MS m/z (ESI): 385.1 [M+l] 'The sixth step l-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazine 丨, ]]]]] 2 95255 302 201242964 ( 5,6-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane- hydrazine, 〗 〖, a different ° 引 °多琳]-2'-yl) ethyl ketone hydrobromide 5',6' _diethoxy-7'-fluoro-spiro [ Propylene _1,3,-isoindole]-indole-imine 41g (26mg, 0.1 mmol) dissolved in imL tetrahydrofuran 'Addition of 2-bromo-l-[3-tert-butyl-5-[4 -(2-Phenylethyl)-indol-1-yl]phenyl]ethanone 103e (38 mg, 0.1 mmol). The reaction mixture was concentrated under reduced vacuo. ～1_yl] phenyl]-2-(5',6,-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, Γ-isoporphyrin] -2'-yl)ethanone hydrobromide 103 (28 mg, white solid), yield: 43.7%. MS m/z (ESI): 566.1 [M+l] 4 awake R (400 MHz, DMSO-' ppm): δ 8·69 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7. 04 (s, 1H), 5. 32 (s, 2H), 4.25 (ro, 2H), 4.14 (m, 2H), 3.60 (m, 2H), 3.27 (m, 2H), 2.71 # (in, 2H), 2.64(ra, 2H), 1.69(ra, 2H), 1. 38 (m, 2H), I.37 (s, 9H), 1.31 (m, 6H) Example 104 1- (3-tert-butyl-5-cyclopropyl-phenyl)-2-(5',6'-diethoxy-4'-end-3'-imino-spiro[cyclopropane-1, Γ-Isoporphyrin]-2'-yl)ethylhydrazine Hydrogenate 303 95255 201242964

41g third step*

Produce

104 First step 1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone 1-(3-bromo-5-tert-butyl-phenyl)ethanone 77d (lg, 3. 90 mmol) and tetrakistriphenylphosphine (450 mg, 0.39 mmol) were dissolved in 60 mL of dioxane, and mixed for 10 minutes, and then 10 mL of cyclopropyl phthalic acid (500 mg, 5.90 mmol) and carbonic acid (6.30) An aqueous solution of g, 19.50 mmol) was added to the reaction system, and the mixture was heated to 90 ° C and stirred for 5 hours. After cooling to room temperature, filtration, 50 mL of ethyl acetate and 10 mL of water were added to the filtrate, and the organic phase was extracted and extracted with a saturated sodium carbonate solution (30 mL×2), dried with anhydrous sulfuric acid, filtered, and concentrated. The residue obtained was purified by eluent column chromatography using eluent column chromatography to give the title product 1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone 104a (600 mg, colorless liquid). Rate: 71.2 ° / 〇. MS m/z (ESI): 217.1 [M+l] Step 2 2-bromo-1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone 1-(3-tert-butyl) 5--5-cyclopropyl-phenyl)-ethanone 104a (540 mg, 2. 50 mmol) was dissolved in 7.5 mL of tetrahydrofuran, and added tridecylphenyl three deserts 304 95255 201242964 ammonium (940 mg, 2 50 mmol), the reaction was stirred for 2 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to afford the title product 2-di-1-(3-tert-butyl-5-cyclopropyl-phenyl)-B Ketone 〇4b (510 mg, colorless liquid), yield: 68.9%. The third step 1-(3-tert-butyl-5-cyclopropyl-phenyl)-2-(5,6'-diethoxy-4'-fluoro-3-imino-spiro[ring丙院_1,1' _异π弓布朵淋]-2'-yl)ethanone hydrobromide salt • 5',6'-diethoxy-7,-fluoro-spiro[cyclopropane- 1,3'-isoindolin-1'-imine 41g (82mg, 0.31mmol) and 2-bromo-1-(3-tert-butyl-5-cyclopropyl-phenyl)-ethanone i 4b (92 mg, 0.31 mmol) was dissolved in tetrahydrofuran, and the reaction was stirred for 12 hours to precipitate a large amount of solid. After suction filtration, the filter cake was washed with EtOAc (EtOAc EtOAc (EtOAc) 6'_Diethoxy_4,fluoro-3'-imino-spiro[cyclopropane-M'-isoindole]_2,_yl)ethanone hydrobromide φ acid salt W4 (139 mg, white solid ), yield: 8 〇. MS </ RTI> </ RTI> <RTI ID=0.0></RTI> 7.53 (s, ijj), 7.48 (sa) 7.03 (s, 1H), 5.20 (s, 2H), 4.27-4.22 (m, 2H), 4.i6_ 4.11 (m, 2H), 2.08-2.05 (m, 1H), l.80 (m, 2I〇, i 66 (m, 2H), 1.41 (m, 3H), 1.33 (s, 9H), i.32 (m, 3H)', h〇3 (m, 2H), 0.78 (m, 2H) Example 105 95255 305 201242964 Bu (3-tert-butyl-5-cyclopropyl-phenyl), 2-(5 6-diethoxy-4n imino-1 , 卜二曱基-异叫卜朵琳一2~基)

First Step 1-(3-tert-Butyl-5-cyclopropyl-phenyl)~2_(56-diethoxy_4_fluoro | Imino-1,1-dimethyl-iso- ah 2-(2-yl)acetamidine with hydrogen oxalate salt 5,6-diethoxy-7-fluoro-3,3-dimethyl-norloxa-bromo 24d (62 mg, 0.21 mmol) was dissolved in 1 mL of tetrahydrofuran In the process, 2_bromo-di(3-tert-butyl-5-cyclopropyl-phenyl)-B is the same as 1〇4b (56 mg, 〇.21 with (4), when the reaction is carried out at 12*. Filtration, The filtrate was concentrated under reduced pressure, and the residue was purified by EtOAc EtOAc (EtOAc) Diethoxy + fluoro_3_imino-1'b dimethyl-iso-dolin-2-yl) acetamidine hydride (10) (10), white solid), yield: 61.0%. MS m/z (ESI): 481.1 [M+l] 7. 55 2H), H NMR (400 MHz, DMSO-' ppm): § 7 π (s (Η) U 1H), 7.51 (s, 1H) , 7.44 (s, 1H), 5.S39 (s, ' 95255 306 201242964 4. 29-4. 23 (m, 2H), 4. 15-4. 10 (m, 2H), 2.07 (m, 1H) H5()(s,6H), h42(m,3H), 1.34 (s, 9H), 1.3 〇 Cm, 3h / 1.02 (m, 2H), 0.80 2H) Example 106 l-[3-tert-butyl -5-(trimethylsulfonyl)-phenyl]_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-dimethyl-isoindoline-2-yl Ethyl ketone hydrobromide

First Step 3-tert-Butyl-5-(trifluoromethyl)benzoic acid 3-Bromo-5-(trifluoromethyl)benzoic acid 106a (5 g, 18.60 mmol) at -78 °C Copper bismuth bromide (178 mg, 0.93 mmol) was dissolved in 50 mL of tetrahydrofuran, and then t-butyl gasification (27.30 mL, 46.50 mmol) was added and the mixture was stirred for 1 hour. The reaction solution was quenched by adding 20 mL of a saturated ammonium chloride solution, and then 20 mL of ethyl acetate and 20 mL of water were added thereto, and the pH was adjusted to 2 to 3 with a hydrogen peroxide solution of 1 Torr, and the aqueous layer was extracted with ethyl acetate. Extraction 307 95255 201242964 (30mLx3), combined organic phase, washed with water (3〇mLx3) and saturated sodium chloride solution (30mLx3) 'dry anhydrous sodium sulfate 'filtered' filtrate concentrated under reduced pressure, eluted with silica gel column chromatography The resulting residue was purified to give the title compound: 3-t-butyl-5-(trifluoromethyl)benzoic acid 106b (3.75 g, yellow solid). MS m/z (ESI): 245.0 [Ml] Step 2 3-tert-butyl-N-decyloxy-5-(trifluoromethyl)benzamide as 3-tert-butyl-5-(3 Fluorinyl benzoic acid 106b (3. 71 g, Φ 15·08 mmol) was dissolved in 25 mL of thionyl chloride, and the reaction was stirred at 85 ° C for 2 hours. The reaction solution was concentrated at 0 ° C, 30 mL of dichloromethane was added, then N-decyloxyguanamine (2. 34 g, 23.98 mmol) was added, and N,N-diisopropylethylamine (5.84 g) was added dropwise. , 45.24 mmol), the reaction was stirred at room temperature for 2 hours. Add 30 mL of water to the reaction solution, extract the liquid, extract the aqueous phase with a gas-fired gas (15 mL×3), and combine the organic phase with water (15 mL×3) and saturated sodium carbonate solution (15 inLx3). Filtration, 'the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent column B to give the title product: 3-tert-butyl-N-methoxy-5-(trifluoromethyl) Formamide 1 〇 6c (985 mg, yellow liquid), yield: 22.6%. MS m/z (ESI): 290.0 [M+1] </RTI> <RTIgt; </RTI> <RTIgt; l-[3-tert-butyl-5-(trifluoromethyl)-phenyl] Base-N-methoxy-5-(trifluoromethyl)benzamide 106c (900 mg, 3.1 mmol) was dissolved in 15 mL of tetrahydro-methane, then 95255 308 201242964 was added methyl magnesium chloride (2. 10 mL, 6 23 mmol), the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding 20 mL of a saturated ammonium chloride solution, and then 15 mL of ethyl acetate and 1 mL of water were added to extract the mixture, and the aqueous phase was extracted with ethyl acetate (15 mL×3), and the organic phase was combined with water (15 mL×3) and The residue was washed with a saturated sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography to afford the title product 1-[3-tert-butyl. 5-(-Trifluoromethyl)-phenyl]ethanone i 〇 6d (720 mg, yellow liquid), yield: 94.7%. 4th step 2-bromo-l-[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone 1_[3-tert-butyl-5-(trifluoromethyl)-benzene The hydrazine was dissolved in 15 mL of tetrahydrofuran, and tridecylphenylammonium tribromide (462 mg, 1.23 mmol) was added, and the reaction was stirred for 1 hour. After the hydrazine, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by hexane column chromatography to afford the title product 2-bromo-1-[3-tert-butyl-5-(trifluorofluorenyl). Phenyl] ketone l 〇 6e (290 mg, yellow liquid), yield: 73.0%. The fifth step 1-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2-(5,6-diethoxy-4-chaos _3_subunit-1,1 -5- 6-diethoxy-7-fluoro-3,3-dimercapto-isoindole-p-amine 24d (115mg, 0.43mmol) was dissolved in 5mL of tetrahydrofuran and added 2-bromo-b[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone i〇6e (i4〇mg, 0.43 mmol ), the reaction was stirred for 1 hour. 5 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (5 mL×2). The organic phase was combined with 309 95255 201242964 and washed with water (10 mL×2) and saturated sodium chloride solution (10 mL×2). The residue was dried over anhydrous sodium sulfate, filtered, and then evaporated. 2-(5,6-diethoxy-4-fluoro-3-imino-1,1-diindolyl-isoindol-2-yl)ethylhydrazine hydrobromide 1〇 6%。 (24mg, yellow solid), yield: 9.4%. MS m/z (ESI): 509.1 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 9.60 (br, 1H), 8. 97 (br, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7. 45 (s, 1H), 5. 56 (s, 2H), 4. 26 (m, 2H), 4. 11 (ra, 2H), 1.52 (s, 6H), 1.40 (m, 12H), 1.32 (m, 3H) Example 107 l-[3-tert-butyl-5-(trifluoromethyl)-phenyl]-2- (5,6,6-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoporphyrin]-2, yl)ethanone oxime bromate salt

First step 1-[3-tert-butyl-5-(trifluoromethyl)-phenyl]_2-(5,6, •diethoxy 310 95255 201242964

Ketone hydrobromide salt 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane_丨,3, _isoporphyrin]-indole-imine 41g (57mg, 〇.22mmol) Dissolved in imL tetrahydrofuran, 2-bromo-l-[3-tert-butyl-5-(trifluoromethyl)-phenyl]ethanone 106e (70 mg, 0.22 mmol). The solid was filtered, washed with EtOAc (EtOAc) (EtOAcjjjjjjjjj Diethoxy-4'-gas-3'-imino-spiro[cyclopropan-1, Γ-iso-bendolin]_2, _yl)ethanone hydrobromide 107 (75 mg, white solid ), yield: 59.1%. MS m/z (ESI): 507.1 [M+l].H NMR (400 MHz, DMSO-i/e, ppm): δ 9.38 (br, 1H), 8.09 (br, 1H), 8.22 (s, 1H) ), 8.15 (s, 1H), 8.05 (s, 1H), 〇3(s, 1H), 5.29(s, 2H), 4. 23 (m, 2H), 4. 12 (m, 2H), 1.86 (in, 2H), 1.66 (in, 2H), 1.39 (m, 12H), 1.31 (m, 3H) Example 108 2~[3-tert-butyl-5-[2-(5',6'- Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethinyl]phenyl]-2-methyl- Propionitrile hydrobromide

311 95255 108 201242964

The first step is 1-(bromoethyl)-3-tert-butyl-5-fluorenyl-stupyl 1-tert-butyl-3,5-diindenyl-benzene 1〇8&amp;(5&amp;,3〇81 1〇1), azo-isobutyronitrile (50mg, 〇·3〇_〇ι) and N-bromosinium imide (4. 39 g, 24.65mmol) dissolved in 5〇mL tetrachloride In carbon, g〇°c disturbed the reaction for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The title product 1-(bromoethyl)-3-tert-butyl-5-methyl-phenyli 8b (6. 10 g, mp. Step 2 2-(3-tert-Butyl-5-fluorenyl-phenyl)acetonitrile The crude 1-(bromoethyl)-3-tert-butyl-5-mercapto-benzene 1 8b (482 mg, 2 mmol And tetrabutylamine cyanide (805 mg, 3 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and the reaction was stirred at 60 ° C for 15 hours. In the reaction mixture, lOinL water was added, and the mixture was extracted with diethyl ether (i〇mLx2). The organic phase was combined, washed with saturated sodium sulfate solution (1 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc. :47. 〇%. Step 3 2-(3-tert-Butyl-5-fluorenyl-phenyl)-2-methyl-propanenitrile Potassium tert-butoxide (198 mg, 176 mm 〇1) was dissolved in 5 at -78 °C In a tetrahydrofuran, 5 mL of a solution containing 2-(3-tert-butyl-5-fluorenyl-phenyl)acetonitrile 108c (150 mg, 0.80 mmol) and iododecane (342 mg, 2.40 mmol) in tetrahydrofuran was added dropwise and stirred. The reaction was carried out for 3 hours at room temperature for 0.5 hours. After adding 5 mL of water, the mixture was extracted with ethyl acetate (5 mL×2), EtOAcjjjjjjjjj Butyl-5-methyl-phenyl)_2-decyl-propanenitrile 108d (151 mg, yellow oil). Step 4 3-tert-Butyl-5-(1-cyano-1 -methyl-ethyl)benzoic acid The crude 2-(3-tert-butyl-5-fluorenyl-phenyl)-2-indole The base-propanenitrile φ 108d (150 mg, 〇·69 mmol) was dissolved in 1. 3 mL of acetic acid 'Add 〇. imL concentrated sulfuric acid and chromium oxide (206 mg, 2.07 mmol), and the reaction was stirred for 2 hours. 20 mL of water and 1 〇mL of acetic acid were added to the reaction mixture, and the extract was separated, and the aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was combined, and then washed with water (i〇mLx2) and saturated sodium hydride solution ( 1 QmL) 'anhydrous sulphuric acid was dried, filtered, and the filtrate was concentrated under reduced pressure to give crude title product: 3-tert-butyl-5-(1-cyano-ethyl-ethyl-ethyl) succinic acid l s 8e (154 mg, yellow oil The product was directly subjected to the next reaction without purification. The fifth step 313 95255 201242964 3-tert-butyl-5-(1-cyano-i-methyl-ethyl)_N_decyloxy- fluorenyl-benzoguanamine will be crude 3-tert-butyl- 5-(1-Cyano-1 -indolyl-ethyl)benzoic acid 108e (154 mg, 0.62 mmol) was dissolved in 2 gasified sulfoxide, 8 (TC stirred for 2 hours). Add 5 mL of dichloromethane, and add N,0-dimethylhydroxylamine hydrochloride (97 mg, 〇99 mm〇1) under ice cooling, and then add N,N-diisopropylethylamine (24 mg,丨.86mm〇l), stirring the reaction 〇. 5 hours. Add 5mL of water to the reaction solution, extract with ethyl acetate (1〇mLx2), combine the organic phase, wash with saturated sodium chloride solution (1〇mL), anhydrous The dried magnesium sulfate was dried over anhydrous EtOAc. -N-Methoxy-N-methyl-benzimidamide i 〇 8f (100 mg, yellow oil), yield: 55.2%. MS m/z (ESI): 289.1 [M+l] Six-step 2-(3-acetamido-5-tert-butyl-phenyl)-2-mercapto-propanenitrile under ice bath '3-tert-butyl-5-(1-cyano-1-methyl) -Ethyl)-N-decyloxy-N-methyl-benzamide 108f (100 mg, 0.34 mmol) was dissolved in 2 mL of tetrahydrofuran' plus 3M methylmagnesium hydride (〇.23mL, 0·68ιηπιο1) The reaction was stirred for 2 hours. 5 mL of water was added to the reaction solution, the pH was adjusted with 2 mL of 1 M hydrogen chloride solution, extracted with ethyl acetate (5 mL×3), and the organic phase was combined and washed with saturated sodium chloride solution (20 mL×2), anhydrous sulfuric acid Magnesium was dried, filtered and the filtrate was concentrated under reduced pressure to give the crude title product, 2-(3-ethyl-ethyl-5-tert-butyl-phenyl)-2-mercapto-propanonitrile, 8 g (75 mg, gray 314 95255 201242964 Color solid), the product was taken to the next step without purification. MS m/z (ESI): 261.2 [M+18] Step 7 2-[3-(2-bromoethyl)-5-tert-butyl __Phenyl]_2_mercapto-propionitrile The crude product 2-(3-acetamido-5-tert-butyl-phenyl)-2-mercapto-propanenitrile 108g (75mg, 0. 30 ugly 1 5小时。 Filtration, the filtrate was concentrated under reduced pressure, using a thin layer, was added to a solution of the hydrazine. Chromatography to purify the residue obtained with Developer System B to give the title . Was 2_ [3_ (2_ bromo-acetyl) -5-tert-butyl - phenyl] -2-yl Yue - i〇8h propionitrile (72 mg of, colorless liquid). Yield: 742%. MS m/z (ESI): 341.1 [M+18] Step 8 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro_3' _Imino-Spirulina [cyclopropane-1, hydrazine-isoporphyrin]-2,-yl)ethinyl]phenyl]_2-methyl-propionitrile hydrobromide 5',6' - Diethoxy-7'-fluoro-spiro[cyclopropane-indole, 3,-isoindoline]-1'-imine 41g (40mg, 0.15mmol) was dissolved in mL.5mL· tetrahydrofuran, added 2- [3-(2-Bromoethenyl)-5-tert-butyl-phenyl]-propan-1-ylpropanenitrile 108h (49 mg, 0.15 mmol). The solid was filtered, washed with EtOAc (EtOAc (EtOAc:EtOAc) 3,-imino-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)ethenyl]phenyl]_2-methyl•'propionitrile hydrobromide 108 (33 mg , white solid), Yield: 44 %. 95255 315 201242964 MS m/z (ESI): 506.1 [M+l] 4 NMR (400 MHz, DMSO-form, ppm): δ 7·97 (s, 1H), 7 93 (s, 1H), 7.88 ( s, 1H), 7.04 (s, 1H), 5.27 (s, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 1.67 (s, 6H), 1.43 (m, 2H), l 39 ( m, 2H), 1.38 (s, 9H), 1.33 (m, 6H) Example 109 2-[3-tert-butyl-5-[2-(5,6-diethoxy-4-fluoro-3) -iminodifluorenyl-isoindole-inducible D-methyl-2-yl)ethinyl]phenyl]-2-indenyl-propionitrile

109

First step φ 1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]-2-(5,6-diethoxy-4-fluoro-3-imino-1 ,1-dimercapto-isoindoline-2-yl)ethanone hydrobromide salt 5,6-ethoxy-7-fluoro-3,3-dimethyl-isoindole 1_Amine 24 (1 (106 mg, 0.40 mmol) was dissolved in 5 mL of tetrahydrofuran, and 2-[3-(2-bromoethyl)-5-tert-butyl-phenyl]-2-indolyl-propanenitrile was added. 1 〇 ( (129mg, 0. 40mmol) 'Stirring reaction for 4 hours. The reaction solution was concentrated under reduced pressure, using a thin layer of color 316 95255 201242964 spectrum chromatography to show _ « A purification plant (four) yu 卜 [3-tert-butyl one 5-(2_Pentylethoxy)phenylindole (10) bis-oxyl-4-fluoro-3-imino-u-dimethyl-iso-bendolin- 2_yl) Acid 〇9 (86 mg, white solid), yield: 36 5%. MS m/z (ESI): 508.3 [M+l] 4 NMR (400 MHz, DMSO-ώ, ppm): δ 8. 〇l (s,in), 7. 98 (s,1H),7.88 (s , 1H), 7.45 (s, 1H), 5.48 (s, 2H), 4.28

(m, 2H), 4. 12(m, 2H), 1.78(s, 6H), 1.44 (s, 6H), 1.40 (m, 3H), 1.38 (s, 9H), 1.31 (m, 3H) Example 110

3-tert-butyl-5-[2-(5,6'-diethoxy_4-carbon-3'-imino-spiro[cyclopropane-1, Γ-isoindole]-2 '-yl)ethinyl]-N,N-bis(2-hydroxyethyl)benzamide hydrochloride

First step 3-tert-butyl-5-[2-(5,6, _diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, 1,-isoindole] Porphyrin]-2'-yl)ethenyldiphenyl N,N-di(2-hydroxyl 317 95255 201242964 ethyl)phenylhydrazine hydrochloride 3-tert-butyl-5-[2-(5, ,6,-Diethoxy-4,-fluoro-3'-imino-spiro[cyclopropane-1,1'-isoindoline]-2,-yl)ethenyl]benzoate Acid salt 76 (350 mg, 0.68 mmol) and 2-(2-hydroxyethylamino)ethanol (142 mg, 1.35 mmol) were dissolved in 3 mL of N,N-didecylamine, and 2-(7-azo) was added. Benzotriazole)-N,N,Ν',Ν'-tetradecylurea hexafluorophosphate (308 mg, 0.81 mmol) was stirred for 2 hours. 5 mL of a saturated sodium chloride solution was added to extract with ethyl acetate (2 mL mL). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography using eluent system A To give the title product 3_tert-butyl_5_[2-(5',6'-diethoxy-4'-fluoro-3,-imino-spiro[cyclopropane-1,1'-iso Porphyrin]-2'-yl)ethinyl]-N,N-bis(2-hydroxyethyl)benzamideamine hydrochloride 110 (11〇11^, pale yellow solid), yield: 22.3 %. MS m/z (ESI): 570.1 [M+l] NMR (400 MHz, DMSO-i/e, ppm): δ 7.99 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H) , 7. 82 (s, 1H), 6. 97 (s, 1H), 5.16 (s, 2H), 4.87 (m, 2H), 4.23-4.15 (m, 2H), 4.13-4.09 (m, 2H) , 3.66(m, 2H), 3.56 (m, 2H), 3. 51 (m, 2H), 3.32 (m, 2H), 1.76 (in, 2H), 1.58 (in, 2H), 1.40 (m, 3H) ), 1.36 (s, 9H), 1.29 (m, 3H) Example 111 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl)ethenyl]-N-[2-hydroxy-1-(hydroxyindenyl)ethyl]benzoguanamine salt Acid salt 318 95255 201242964

搴Step 1 3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fail-3'-imino-spiro[bad propyl-1,1' - ° 弓 朵 朵 ] ] ] -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 ] ] ] ] ] ] 3- 3- 3- 5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, fluorenyl-isoindoline]-2'-yl) Benzoyl benzoate hydrochloride 76 (150 mg, 0.29 mmol) and 2-aminopropyl-1,3-diol (53 mg, 〇. 58 mmol) were dissolved in 1 mL of N,N-dimethylformamidine To the amine, 2-(7-azobenzotriazole)-n, hydrazine, hydrazine, Ν'-tetramethyluronium hexafluorophosphate (132 mg, 0.25 mmol) was added, and the reaction was stirred for 2 hours. Add 5 mL of saturated sodium carbonate solution, extract with ethyl acetate (2 〇mLx2), combine the organic phase, dry the anhydrous 'sulfuric acid' filter, concentrate under reduced pressure, and purify the residue by eluent column chromatography with eluent column system A. To give the title product 3_tert-butyl_5_[2-(5,6-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-oxime, ι'-isoindole] Phenanyl]-2'-yl)ethenyl]hydroxyl_ι_(hydroxymethyl)ethyl]benzamideamine hydrochloride 111 (12 mg, pale yellow solid), yield: 7 〇·〇%. 319 95255 201242964 MS m/z (ESI): 556.2 [M+l] 4 NMR (400 MHz, DMS0-i/6, ppm): δ 9.47 (br, 1H), 9.03 (br, 1H), 8.45-8.42 (m, 2H), 8.25 (s, 1H), 8.08 (s, 1H), 7.02 (s, 1H), 5.36 (s, 2H), 4.77 (m, 2H), 4.25 (m, 2H), 4. 13(m, 2H), 3. 59 (m, 4H), 1.84(m, 2H), 1.65 (m, 2H), 1.41 (m, 3H), 1.39 (s, 1H), 1.32 (m, 3H) Example 112 l-[3-tert-Butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy-4-fluoro -3-imino-1,1-dimethyl-isoindol-2-yl)ethanone hydrobromide

103e 112 OH First step l-[3-tert-butyl-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-2-(5,6-diethoxy- 4-fluoro-3-imino-1,1-dimercapto-isoindol-2-yl)ethanone hydrobromide 5,6-diethoxy-7-fluoro-3, 3 -Dimethyl-isoindole-abamine 24d (56 mg, 0.20 mmol) was dissolved in 5 mL of tetrahydrofuran, and 2-bromo 320 95255 201242964 -l-[3-tert-butyl-5-[4- (2-Hydroxyethyl)piperazine-indolyl]phenyl]ethanone 103e (80 mg, 0.20 mmol) and triethylamine (80 mg, 0.20 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -yl]phenyl;|_2_(5,6-diethoxy-4-fluoro-3-imino-1,1-diindenyl-isoindoline-2-yl)ethanone hydrobromide 2%。 Salt 112 (21mg, yellow solid), yield: 16. 2%. MS m/z (ESI): 569.7 [M+1]

4 NMR (400 MHz, DMSO-form, ppm): δ 7. 22 (s' 1H), 6 93 (s, 1H), 6.74 (s, 1H), 5.48 (s, 2H), 4.27 (m, 2H) ), 4. 12 (m, 2H), 3. 62 (in, 2H), 3. 44 (m, 4H), 3. 22 (m, 4H), 2 53 (in, 2H), 1.32 (m, 6H), 1.35 (s, 9H), 1.27 (s, 6H) Example 113 1-[3-tert-butyl-5-(1,2-di-diylethyl)phenyl]- 2-(5' ,6, _2; oxy-4'-fluoro-3'-imino-spiro[cyclopropan-1,1,-isoindole 2,yl)ethanone hydrobromide

First Step 1-(3-tert-Butyl-5-vinyl-phenyl)ethanone 321 95255 201242964 1-(3-Bromo-5-tert-butyl-phenyl)ethanone 77d (360 mg, 1.41 mmol) And tetrakis(triphenylphosphine) (163 mg, 0.14 mmol) was dissolved in 4 mL of dioxane, stirred for 10 minutes, and then added tri-n-butyl (vinyl) tin (492 mg, 1.55 mmol) and 1铯 (428, 2. 82 mmol), 9 (TC 槚: mixed reaction for 2 hours. Add 5 mL of water and 1 mL of ethyl acetate to the reaction mixture, extract the liquid, dry the organic phase with anhydrous sulfuric acid, filter, filter, The liquid was concentrated under reduced pressure and purified tolulujjjjjjjjjjjjjjjjjj 7 mg, colorless oil) The product was taken to the next step without purification. MS m/z (ESI): 203.1 [M+l] The second step l-[3-tert-butyl-5-(1,2 -dihydroxyethyl)phenyl]ethanone The crude 1-(3-tert-butyl-5-vinyl-phenyl)ethanone U3a (404 mg, 2 ιμ〇1) was dissolved in 10 mL of tert-butanol, followed by Human N-methyl-N-oxidin (257 mg, 2.20 mmol) and iron tetraoxide (25 mg O.lOmm) (ol), stir the reaction for 1 hour. Add the solution of pyridinium (tetra) sodium thiosulfate and 20 mL of ethyl acetate in the reaction mixture, and wash the organic phase with saturated sodium chloride solution (5 mL×2). Dry with anhydrous magnesium sulfate, filter, filtrate Concentration under reduced pressure, the residue obtained was purified eluting elut elut elut elut elut elut elut elut elut Steel 113b (182 mg, colorless oil), yield: 38. 〇〇/. MS m/z (ESI): 237.1 [M+l] Step 3 2-Moss [3-tert-butyl-5 -(l,2-di-diethyl)phenyl]acetamethylene 95255 322 201242964 1-[3-tert-Butyl-5-(1,2-dihydroxyethyl)phenyl]ethanone 1131) ( 180 mg, 0.76 imn 〇l) was dissolved in 2 mL of tetrahydrofuran, tridecylphenylammonium tribromide (287 mg, 0.76 mm 〇l) was added, and the reaction was stirred for 4 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title product 2-bromo-tert-butyl-5-(1,2-dihydroxyethyl)phenyl]ethanone 113c (30 mg, colorless liquid), yield: 12·5%. The fourth step 1-[3_tert-butyl-5-0,2-dihydroxyethyl)phenyl]-2-(5,6, _diethoxy-4'-fluoro-3'- Amino-spiro[cyclopropane-indole, anthracene, -isoporphyrin]_2,-yl)ethanone hydrobromide salt 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane _1,3, _isoporphyrin]-indole-imine 41g (25mg, 0.1 mmol) was dissolved in mL.5mL of tetrahydrofuran, and 2-bromo-1-[3-tert-butyl-5-(1) was added. , 2-Dihydroxyethyl)phenyl]ethanone 118c (30 mg, 0.1 mmol). After suction filtration, the solid was washed with tetrahydrofuran (0.5 mL×3) &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; tert-Butyl-5-(1,2-di-transethyl)phenyl] •~2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[ 0%。 Cyclopropane &lt;, γ-isoindoline]-2'-yl) ethyl ketone hydrobromide 113 (10 mg, white solid), yield: 18. 0%. MS m/z (ESI): 499.2 [M+l], NMR (400 MHz, DMSO-i/e, ppm): δ 7.87 (s, 1H), 7 83 (s, 1H), 7.73 (s, 1H), 7.01 (s, 1H), 5.49 (s, 1H), 5.25 (s, 2H), 4. 88(s, 1H), 4. 22 (m, 2H), 4. 12 (m, 2H) , 3.49 95255 323 201242964 (m, 2H), 1.76 (m, 2H), 1. 62 (m, 2H), 1.40 (m, 3H), 1.34 (s, 9H), 1.31 (m, 3H) Example 114 2-[3-tert-butyl-5-[2-(5,6'-diethoxy-4,-fluoro-3,-imino-spiro[cyclopropane-1, oxime-isoindole] Porphyrin]_2'-yl)ethenyl]phenyl]-2-methyl-propionic acid hydrobromide

The first step 2-(3-acetamido-5-tert-butyl-phenyl)-2-mercapto-propionic acid formazan is intended for 1-(3-bromo-5-tert-butyl-phenyl)ethyl Ketone 77d (4.27 g, 17 mmol), bis(dibenzylidenepropene)la (96 mg, 0.17 mmol) and zinc hydride (866 mg, 8.37 mmol) dissolved in 40 mL of N,N-dimethylformamide Add 1-methoxy-2-methyl-1-(tridecyloxy)propene (4.35 g, 25 mmol) and tri-tert-butylphosphine (1.69 g, 〇.84 mmol), 10 (TC stirring) The reaction was carried out for 16 hours. 5 mL of water was added to the reaction mixture, and extracted with ethyl acetate (50 mL×3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. B Purification of the obtained residue to give the title product 2-(3-ethyl-decyl-5-tert-butyl-phenyl)-2-indolyl- 324 95255 201242964 decyl propionate 114a (1.68 g, brownish yellow oil ), yield: 36 2%. Second step 2-[3-(2-bromoethyl)-5-tert-butyl-phenyl]-2-methyl-propionic acid methyl vinegar 2-(3 -Ethyl-5-tert-butyl-phenyl)-2-mercapto-methylacetonate 114a (276 mg, 1 mmol) was dissolved in 5 mL of tetrahydrofuran, and phenyldimercaptoammonium bromide (376 mg, 1 mmol) was added. , The mixture was stirred for 1 hour. After the mixture was evaporated, the mixture was washed with ethyl acetate (10 mL), and the organic phase was combined and concentrated under reduced pressure. [3-(2- oxaethyl)-5-tert-butyl-phenyl]-2-methyl-propionic acid decyl ester 114b (154 mg, pale yellow liquid), yield: 43.4%. -[3-tert-butyl-5-[2-(5,6-diethoxy-4'-fluoro-3,-imino-spiro[cyclopropane-1,1'-isoporphyrin] -2'-yl)ethinyl]phenyl]-2-methyl-propionic acid hydrobromide 5,6-diethoxy-7'-fluoro-spiro[cyclopropane-i,3, - αα弓布朵琳] φ _1'_imine 41g (92mg, 0. 35mmol) was dissolved in 3mL tetrahydrofuran, added 2_[3-(2- ethethyl)-5-tert-butyl -Phenyl]-2-mercapto-indolyl propionate 114b (124 mg, 0.35 mmol) and triethylamine (〇. 5 mL, 0.35 mmol), stirred for 8 hours. The reaction was concentrated under reduced pressure and chromatographic column chromatography Purification by eluent system A gave the title product 2-[3-tert-butyl-5-[2-(5',6'-diethoxy-4'-fluoro-3'-imino-- Snail [cyclopropane-1,1,一吲哚吲哚琳]-2'- Ethyl phenyl] phenyl]-2-mercapto-propionic acid hydrobromide salt U4 (13 mg, yellow solid), yield m MS m/z (ESI): 525.2 [M+l] 325 95255 201242964 WNMRMOOMHz , DMSO-ice, ppm): 6 10.98 (br, 1H), 8. 19 (br, 1H), 8.02 (br, 1H), 7.48 (m, 2H), 7.30 (s, 1H), 6.88 (m, 1H), 5. 24 (s, 2H), 4. 16 (m, 2H), 4. 02 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.53 (s, 6H) , 1.40-1.23 (m, 15H) Example 115 l-[3-tert-Butyl-5-(2-hydroxy-1,di-diyl-ethyl)phenyl]_2-(5',6'- Diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane_i,i,-iso

°引过淋淋]-2'-based) acetamidine hydrochloride

First Step 2-[3-tert-Butyl-5-(1,1-dimethoxyethyl)phenyl]-2-indolyl-propionic acid decyl ester

2 _( 3 _Ethyl-5-tert-butyl-benzyl)-2-methyl-propionic acid hydrazone 114a (600 mg, 2. 17 mmol) was dissolved in 5 mL of methanol, and trimethoxy decane was added. (714 uL, 6.51 mmol) and camphorsulfonic acid (5 mg, 〇. 22 mmol), and the reaction was stirred for 3 hours. To the reaction mixture, 50 mL of water and 40 mg of potassium carbonate were added, and 326 95255 201242964 was extracted with ethyl acetate (30 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous magnesium sulfate The crude title product 2-[3-tert-butyl-5-(1,1-dimethoxyethyl)phenyl]-2-indolyl-propionic acid methyl ester ii5a (676 mg, brown red oil) The product was directly subjected to the next reaction without purification. The second step 1-[3-tert-butyl-5-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]ethanone will be the crude 2-[3-tert-butyl-5-(1) , 1-Dimethoxyethyl)phenyl]-2-methyl-propionic acid methyl ester 115a (670mg, 2.08mmol) was dissolved in 5mL of tetrahydroanthracene alpha, and added to the hydrogenated chain (87mg). , 2.29mmol), sandalwood reaction for 10 minutes. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with a saturated sodium chloride solution (1 mL mL), dried over anhydrous magnesium sulfate, filtered, 60 Μ Hydrogenated dioxane solution, stirred for 5 minutes. To the reaction mixture, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3 mL mL), and the organic phase was combined, washed with a saturated sodium sulfate solution (100 mL×2), dried over anhydrous magnesium sulfate, filtered and evaporated The title product 1-[3-tert-butyl-5-(2-hydroxy-1'-dimethyl-ethyl)phenyl]ethanone 115b (471 mg, sm. One step reaction. The third step 2 'sn-tert-butyl _5_(2-pyridyl-1,1-dimercapto-ethyl)phenyl] b will be the crude 1-[ 3-tert-butyl-5-(2-trans-based) -1,1-Dimethyl-ethyl)phenyl]B-115b (471mg, 1.90mmol) was dissolved in i〇mL tetrahydrofuran 95255 327 201242964, adding phenyl trimethyl desertification money (713mg , 19〇 followed by 1), stir the reaction for 0.5 hours. After filtration, the mash was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to afford the title product 2 succinic [3-tert-butyl-5-(2-hydroxy-1,1-dimethyl 4%。 _Ethyl) phenyl] ethyl ketone 115c (170mg 'light yellow liquid) 'yield: 27. 4%. MS m/z (ESI): 327.0 [M+l] Step 4 l-[3-tert-butyl-5-(2-hydroxy-1,1-didecyl-ethyl)phenyl]_2-( 5,6-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-oxime, one iso- ̄ ° °Doluo]-2'-yl) ethyl ketone hydrobromide 5',6'-diethoxy-7'-fluoro-spiro[cyclopropane-oxime, 3'-isoporphyrin]-1'-imine 41g (120mg, 0.46mmol) dissolved in im[tetrahydrofuran 2-Bromo-1-[3-tert-butyl-5-(2-hydroxy-1,1-didecyl-ethyl)phenyl]ethanone 115c (164 mg, 0·50 mmol) was added and stirred. 12 hours. Filtration of the 'cakes with tetrahydrofuran wash (lmL) 'vacuum dried to give the title product 1-[3-tert-butyl-5-(2-hydroxy-1,1-didecyl-ethyl)phenyl ]_2-(5',6'-diethoxy-4'-fluoro-3'-imino-spiro[cyclopropane-1, anthracene, an iso-sigma 引 °多琳卜 2'-yl) The ketone hydrobromide 115 (190 mg, white solid), Yield: 70.6%. MS m/z (ESI): 511.2 [M+l] 4 NMR (400 MHz, DMSO- ice, ppm): δ 9.41 (br, 1H), 9. 10 (br, 1H), 7.82 (s, 1H) , 7.80 (s, 1H), 7.76 (s, 1H), 7. 04(s, 1H), 5. 25(s, 2H), 4.23 (in, 2H), 4. 12 (m, 2H), 3 . 49 (m, 2H), 1.76 (m, 2H), 1.66 (m, 2H), 1.40 (m, 3H), 328 95255 201242964 1.35 (s, 9H), 1.31 (m, 3H), 1.28 (in, 6H) Test Example: Biological Evaluation Example 1 I Bow Ion Transport Inhibition Experiment The following method can be used to determine the inhibitory effect of the compound of the present invention on PAR1 mediated calcium ion transport. By using Chinese hamster ovary cells CH0-K1 (purchased from the Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, catalogue GNHa 7) 'Froo-4 NW calcium assay kit (invitrogen Cat. No F36206) and PARI agonist polypeptide thrombin receptor activator Peptide 6 (Sigma, T1573-5MG) was used to determine the effect of the inventive compounds on PARI-mediated calcium transport. The probenecid stock solution and the loading buffer (i〇ading buffer) required in the experiment can be prepared according to the instructions of the Flu〇_4 NW calcium assay kit. Experimental procedure: CH0-K1 cells were seeded with DEME medium (Gibco) with 10% fetal bovine serum as complete medium and seeded into 96-well cell culture plates at a concentration of 25,000 cells/well at 37. (:, 5% carbon dioxide culture until confluence. Then discard the medium, add the L-loaded loading buffer to each well of the plate, and incubate for 45 minutes at 37 ° C, 5% carbon dioxide. The compound was first dissolved in dimethyl sulfoxide, and then diluted to the desired concentration for the experiment using an assay buffer (containing IX HBSS, 20 mM HEPES, 2.5_pronececid), and then added to each well of the test group on a 96-well plate. l〇0uL diluted test compound sample, negative pair 95255 329 201242964 Add the same volume of assay buffer to the group. The plate was then incubated for 30 minutes at room temperature. Then add 25 # L buffer (lx) to each well. HBSS, 20 mM HEPES) diluted to 20 μM of thrombin receptor activator peptide 6. The relative fluorescence intensity of each well was measured at an excitation wavelength of 485 nm and an emission wavelength of 525 nm. The inhibition rate of the guided ion transport. The inhibition rate of the test compound for PAR1 is calculated by the following formula: IR = (Fnc-ftc) / Fnc%

Fnc: Fluorescence intensity of the negative control well FTC·Fluorescence intensity of the test compound well The half-inhibitory concentration of the test compound I C 5 0 can be calculated by the inhibition rate at different concentrations. Number of the implementation compound ICso (CH0-K1)/^M -----§__ 0.032 s 14 — 0. 018 ___15 -----0. 035 -_ 16 0. 022 ^ 18 0. 027 .-__^ 19 0.023 ^ 20 0. 017 -_ 22 0. 022 -^24 0. 034 -_ 26 0.021 -__ 0.047 ___30 0. 072 ^ 34 _0.049 -_ 35 0. 027 .41 0. 006 -_ 42 0. 038 330 95255 201242964 44 0. 046 51 0. 065 68 0. 099 69 0.071 70 0. 034 72 0. 088 75 0. 074 88 0. 037 89 0. 036 90 0. 01 93 0.013 96 0. 033 97 0. 035 100 0. 058 101 0. 077 102 0. 038 103 0. 046 104 0. 03 108 0. 029 109 0. 042 115 0. 025 116 0. 003 120 0. 014 Conclusion: Ben The value of the calcium flux inhibition rate of the test compound is from 0.001 to 0. 099 # M, and the compound of the present invention has a significant inhibitory effect on PAR1 mediated calcium ion transport. Example 2 In vitro platelet aggregation test The following method can be used to determine the inhibitory activity of the compound of the present invention on platelet aggregation. The experimental methods are briefly described as follows: 331 95255 201242964 ACD was used as an anticoagulant to obtain whole blood samples from healthy male guinea pigs (purchased from Shanghai Shengwang Experimental Animal Farm) (body weight 450 to 600 g) by venipuncture. Platelet-rich plasma was then obtained by centrifugation at 200 xg for 20 minutes at room temperature. The plasma was then centrifuged at 8 〇〇 xg for 1 minute to the platelet sink. Using Tyre's solution Tyr〇de's buf fer (containing 140 mM NaCl, 2.7 mM KC1, 12 mM NaHCOs, 0.76 mM NaHP04, 5.5 mM Glucose, 5 mM HEPES, 2 mg/mL bovine serum albumin, and pH 7.4, 20 μg/ After washing twice with mL apyrase), the platelet sink was resuspended and calculated, and finally diluted to 2xl 〇 8 to 3x108 cells/mL for use. The agglutination experiment was carried out at room temperature. A 90 wL platelet suspension was first added to each well of a 96-well plate. After the test compound was dissolved in disulfoxide to prepare the concentration required for the experiment, 8 μl of the compound was added to the wells of each test group, and the negative control group was replaced with the same volume of DMS0. Compounds and platelets were pre-incubated for 6 minutes, and then a 2-hearted clotting enzyme stimulating polypeptide TRAP' was added to each well. 96 wells were shaken vigorously on a shaker to initiate the agglutination process. The agglutination rate was obtained by measuring the light transmittance of each well at 4Q5 nm. The platelet aggregation rate of the 'Bay' compound is calculated by the following formula: AR = (Tc - T0) / (T100 - T0)%

Tc: Transmittance of test compound pores T0: Transmittance of negative control wells T100: Transmittance of blank wells The platelet-suppressed agglutination ICSQ values of α-forms can be calculated from the aggregation rates at different concentrations. 95255 332 201242964 Number of the compound of the example I C5Q (platelet aggregation) / # Μ 24 0. 071 35 0. 193 41 0. 033 42 0. 072 Conclusion: The test compound of the present invention has a significant inhibitory effect on platelet aggregation in guinea pigs. Pharmacokinetic Evaluation • Test Example 1 Pharmacokinetic test of the compound of the present invention 1. Abstract The concentration of the drug in plasma at different times after the compounds of Examples 24, 35, 40, 44 and 108 of the present invention were studied. The pharmacokinetic behavior of the compounds of the present invention in rats was investigated and their pharmacokinetic characteristics were evaluated. 2. Test protocol 2.1 Test drug Examples 24, 35, 40, 44 and 108 compounds 2.2 Experimental animals 20 healthy adult SD rats, male and female, divided into 5 groups, purchased from Shanghai Xipuer-Beikai experiment Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016. 2. 3 Drug preparation Weigh the appropriate amount of the drug, add 0.5% sodium carboxymethyl cellulose to grind until the sample is evenly suspended, the sample concentration is 2. Omg / mL reserved for use. 2. 4 Administration 333 95255 201242964 SD rats were intragastrically administered overnight after fasting. The dose was 20. Omg/kg retention (in terms of prototyping)' dose volume l〇mL/kg. 2. 5 sample collection of each group of animals before and after the administration of 1. 0, 2. 0, 3. 0, 4 · 0, 6.0, 8.0, 12.0, 24. 0, 36. 0, 48. 0 The blood was collected from the eyelids by 0. lmL' in a heparinized test tube, and the slurry was separated by centrifugation at 3500 rpm for 1 minute, and stored at -20 °C. Eat 2 hours after administration. 3. Operation: Take 20/L of each plasma of rats at each time after administration, add internal standard solution (100 ng/mL, sterol preparation) 50 # L, sterol 95 /ZL 'vortex mixing for 3 minutes' centrifugation After 1 minute (13,500 rpm), the supernatant was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2. 0 software. Pharmacokinetic parameters results The pharmacokinetic parameters of the compounds of the present invention are as follows: Example No. Drug metabolism experiment (20 mg/kg) Peak concentration curve Half-life retention time Clearance Apparent distribution volume Cmax (ng/mL) AUC(ng/mL*h) tl/2(h) MRT(h) CL/F(l/h/ke) Vz/F(l/kg) 318+25 6980±1366 6.19+0.42 18.5+2.4 2.96+ 0.66 26.6+7.4 303+33⁄4 6837±1062 8.86+0.24 15.9+1 3 2.99+0.52 38.1+5.8 —il— 279+47 2841+350 4.19+0. 64 108 , , , c 112+43 2341±866 9. 96+1.75 _'·4ο±υ.45 7.12+0.87 42.7+6.2 ^.1+3.6 9.73+4.43 141+74 4001210 (l〇mg/kg, help, L-fV]__ i: Taifa 3883± 1098 明消丨读.1. - ------- 10.7+3.2 2.78+1.00 43.0+18.3 Pharmacological test 95255 334 201242964 Objective: To test the PAR-1 inhibitor compound 44 compound for TARP induction Effect of platelet aggregation rate of guinea pigs Experimental drug: Compound of Example 44; Prostaglandin I2, TRAP was supplied by Sigma. Experimental method: Drug dosage was 50 mg/kg (2.5 ml/kg) 'With 0.5% carboxymethylcellulose Sodium plus 5% Tween-80 Suspension, male guinea pigs weighing 250 g to 350 g 'randomized, intragastric administration, 2 months after returning to the original cage, anesthetized with 20 / urethane 'pulse air abdominal aorta blood collection using a disposable plastic syringe, Containing 3.8% sodium citrate (i: i〇 volume, one citrate and nine blood anticoagulation) ^ Preparation of platelet-enriched plasma: guinea pig abdominal aorta blood with 2 〇〇g speed After centrifugation for 10 minutes (22. 〇, the upper platelet-enriched plasma was taken out 1.5 mL.

^ Small board washing method: use Mode, s buffer, s〇lution

mM, KC1 2. 8 mM, KH2P〇4 〇. 8 mM, MgCh 0. 8 mM, NaHC 8*9 mM 'HEPES 10 ^ glucose 5.5 mM) 〇/plate aggregation experiment. Platelet aggregation assay, platelet buffer $ Add U1 β L to the transparent plastic &amp; you, in the cuvette, add 3/zL sea rush and ML calcium chloride 酽, in the cuvette. , υβΜ) 'Add a magnetic stirrer at 37 ° C for 2 minutes, then add jfj A]r row continuous (four) platelet aggregation inducer TMP, the most Mm sag change rate (1 minute, 3 minutes, 5 Minute (four) rate) to evaluate the inhibition of drug platelet aggregation. 95255 335 201242964 Experimental results: The compound of Example 44 has a strong inhibitory effect on TRAP-induced platelet aggregation in guinea pigs within 5 minutes, and the compound of Example 85 (i〇mg/kg) was compared at 3 minutes, 5 compared with the blank control group. The decrease in the percentage of aggregation at 4:47% and 45.21% (P&lt;0.05, P&lt;0.05); the decrease in the percentage of aggregation at 3 minutes and 5 minutes at SHR130362 (30 mg/kg) was 57.63% and 48. 57% (P&lt;0. 05, P&lt;0·05); SHR130362 (50mg/kg) The percentage of aggregation reduction at 1 minute, 3 minutes, and 5 minutes is 69. 96%, 82.55%, and 78. 51% (P &lt; 0.05, P &lt; 0. 0 (H, P &lt; 0.001). Therefore, the compound of Example 44 has a better anticoagulant effect. [Simplified illustration] 〇 [main components Explanation of symbols] None. 336 95255

Claims (1)

201242964 VII. Patent application scope: 1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, Wherein: Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further substituted by one or more substituents of Ra as needed; Y is selected from -CR12- or N atom; L is selected from -CRl3Rl4 ~ or - (cm-; R, R2 and R3 are each independently selected from the group consisting of a hydrogen atom, a hydrazine, a hydroxy group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group , aryl, heteroaryl, -(:(〇)〇1^,_0C(0)Rl5, _〇(CH2)nC(〇)〇Rl5: -(CH〇nC(0)〇R15,-c( 〇) R15, -NHC(〇)Ri5, _s(〇)pRl5, -NR16R17, -〇C(〇)NR16R17, -C(0)NR16R17 or -S(0)0NRLR17, wherein the alkoxy group, alkyl group , cycloalkyl, heterocyclyl, aryl or heteroaryl is required to be further selected from one or more selected from the group consisting of dentate, thiol, cyano, schlossyl, alkoxy, alkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(0)OR15, -〇C(0)R15, -〇(CH2)nC(0)〇R15, -(CH2)nc(〇)〇Rl5, -C(0 Substituting R15, -NHC(0)R15, -S(〇)pR15, -NR16R17, -〇C(〇)Nr16r17 or -c(o)nr16r17; R1 and R2 or R2 and R3 are attached The carbon atoms together form an aryl group, Wherein the aryl group is further further selected from one or more selected from the group consisting of halogen, 1 95255 201242964, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15, -〇c(〇)R15,-0(CH2)„C(0)0R15, -(CH2)„C(0)0R15, -C(0)R15, -NHC(0) Substituting R15, _S(0)PR15, -NR丨I&quot;, -〇C(8)NR16R17, -c(8)NR丨6R17 or -S(0)0NR16R17; R4 and R5 are each independently selected from cyano, alkoxy, alkane a group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further selected from one or more as needed Peptide, thiol, nitro, cyano, aryl, aryl, heteroaryl, _C(〇)〇R15, -0C(0)R15,-0(CH2)nC(0)0R15, -(CH2 nC(0)0R15, -C(0)R15, -NHC(0)R15 ' -S(0)pR15 &gt; -NR16R17 &gt; -〇C(0)NR16R17 ' -c(o)nr16r17 or -s Substituting (取代) a substituent of 〇nr16r17; or 'R4 and R5 together with a carbon atom to which they are bonded form a cycloalkyl group, wherein the cycloalkyl group is further further selected from one or more selected from halogen, Substituted by a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR16R17; R6 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, Aryl, heteroaryl, -C(0)0R15, -c(〇)R15 or -c(o)nr16r17, wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further Substituted by one or more substituents selected from the group consisting of dentate, hydroxyl, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclic; Ra may be the same or different and each independently selected from a hydrogen atom , hydroxy, halogen, cyano, nitro, decyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(〇)〇R15, 2 95255 201242964 -0C(0)R15,-0(CH2)nC(0)0R15, -(CH〇nC(0)〇R15,,c(〇)Rl5, -NHC(0)R15 ^ -S(0 pR15 &gt; -NR,6R17 &gt; -0C(0)NR,6R^ . -C(0)NR16R17 or -S(0)0NR16R17, wherein the decyl group, alkoxy group, alkyl group, dilute group, alkyne a group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, further optionally one or more selected from the group consisting of halogen, hydroxy, cyano, Alkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl, -C(0)0R15, -0C(0)R15,-0(CH2)nC( 0) 0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(〇)pR15, -NR16R17, -0C(0)NR16R17, -C(0) Substituted by a substituent of NR16R17 or -S(0)0NR16R17; R12 is selected from the group consisting of a halogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic group. , aryl, heteroaryl, -C(0)0R15, -0C(0)R15, -〇(CH2)nC(0)〇R15, -(CH2)nC(0)0R15, -C(0)R15 , -NHC(0)R15, -S(〇)pR15, -nr16R17, -0C(0)NR16R17, -C(0)NR16R17 or -S(0)〇NR16R17, wherein the alkoxy group, alkyl group, ring An alkyl group, a heterocyclic group, a aryl group or a heteroaryl group may be further selected from one or more selected from the group consisting of a pixel, a light group, a cyano group, a decyl group, an alkoxy group, a fluorenyl group, a cycloalkyl group, and a heterocyclic group. , aryl, heteroaryl, -c(o)or15, _〇c(〇)Rl5, -0(CH2)nC(0)0R15, ~(CH2)n(X〇)〇R15, -C(〇 Substituting a substituent of Rl5, -NHC(0)R15, -S(0)PR15, -NRi6Rn, _〇c(〇)nRi6R17, -c(o)nr16r17 or -S(0)0NR16R17; R13 and R14 are each independently selected from the group consisting of an alkyl group or a dentate, wherein the alkyl group is further substituted with one or more substituents selected from a halogen, a hydroxyl group, a cyano group or a nitro group as needed; 95255 3 201242964 R15 is selected from a hydrogen atom. An alkyl group, a cycloalkyl group, a heterocyclic group, or an aromatic aryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further required to be further selected from one or more selected from the group consisting of halogen and hydroxyl groups. Substituted with a substituent of an aryl group, a diyl group, an alkoxy group or a decyl group; R and R are each independently selected from a hydrogen atom, a halogen, a decyl group, an alkoxy group, a % alkyl group, a hetero group, a aryl group or a heteroaryl group, wherein the alkyl, cadaverine, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a hydroxyl group, a hydroxyl group, a cyano group, a nitro group, and an alkoxy group. Base, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, _c(〇)〇Ri5, -0C(0)R15, -〇(CH2)nC(0)〇R15, —(CH2) nC(0)0Ri5, _c(〇)Rl5, -NHC(0)R15, _S(0)pR15, -NR18R19, _〇c(〇)NR18R19, -C(0)NR18R19 or -S(0)0NR18R19 Substituted by a substituent; or 'R16 and R17 The linked nitrogen atom forms a heterocyclic group, wherein the heterocyclic group contains one or more N, fluorene or 5 (fluorene) 1) heteroatoms, and the heterocyclic group is further protected by one or more halogens, Hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -(:(〇)〇{^, __〇c(〇 Rl5, _〇(CH2)nC(;〇)〇Rl5, _(CH2)nC(〇)〇R15, -C(〇)R15, _NHC(〇)Ri5, _s(〇)pRl5, -NR R, Substituted by a substituent of 〇C(〇)NR18R19, _c(〇)nr18r194_s(〇)〇nr18r19; R and R are each independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, a ring-based group, a heterocyclic group, an aryl group. Or heteroaryl; m is selected from 1, 2 or 3; η is selected from 1, 2 or 3; and 4 95255 201242964 p is selected from 0, 1 or 2. 2. a compound of the formula (II) or a pharmaceutically acceptable salt thereof, Wherein: Υ is selected from -CR12- or a ruthenium atom; • L is selected from -CR13R14- or -(CH2)m-; R1, R2 and R3 are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a nitrogen group, a nitro group, and a halogen Oxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(Χ0)0Κ15,-0(:(Ο)Κ15, -〇(χΐί2:)η( Χ0)〇ι^, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(〇)pRi5, -nr16r17, -oc(o)nr16r17, -C( 0) NR16R17 or -S(〇)〇NRi6Rn, wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further selected from one or more selected from the group consisting of halogen and , cyano, schishyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15' -0C(0)R15 &gt; -0(CH2)nC( 0) 0R15 &gt; -(CH2)nC(〇)〇R15. -C(0)R15, -NHC(0)R15, -S(0)PR15, -NR16R17, -〇C(〇)NR16Ri7 or -c Substituting (o) a substituent of nr16r17; R1 and R2 or R2 and R3 together with the carbon atom to which they are bonded form an aryl group, wherein the aryl group is further further selected from one or more selected from the group consisting of halogen, thiol, cyano, Jingji, alkoxy, hospital , cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)0R15, -〇C(〇)R15, -〇(CH2)nC(〇)〇R15, 5 95255 201242964 —(CH2) nC(:0)0Rl5, ~C(0)R15, -NHC(0)R15, -S(0)PR15, _nr16rW, -〇c(〇)NR16R17, -C(0)NR16R17 or -SCO^NW Substituted by a substituent; R4 and R5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkano, cycloalkyl, The heterocyclic group, aryl or heteroaryl group is further optionally one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)0R15, -0C ( 0) Rl5, -0(CH2)nc(0)0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(〇)pr15, _NRi6Rl7, _〇 Substituting a substituent of c(〇)nr16r17, -C(0)NR16R17 or -S(〇)〇NR16R17; or, R4 and R5 together with a carbon atom to which they are bonded form a cycloalkyl group, wherein the cycloalkyl group is optionally required Further substituted with one or more substituents selected from halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl or _NRi6Rn; R6 is selected from hydrogen a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)0R15, -c(〇)R15 or -(X〇)NR16R17, wherein the alkyl group, the alkoxy group The base, cycloalkyl, aryl or heteroaryl group is further optionally substituted by one or more substituents selected from halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclic groups. Substituting; R7, R8, R9, IT and R&quot; each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a decyl group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkyl group, Hetero, aryl, heteroaryl, _C(〇)〇R15, -0C(0)R15, _0(CH2)nC(〇)〇R15, -(CH2)nC(0)0R15, -C(0 R15, -NHC(0)R15, -S(〇)pR15, -NR16R17, -〇c(0)NR16R17, 6 95255 201242964 -c(o)nr16r17 or -S(0)0NR16R17, wherein the decyl group, Alkoxy, alkyl, dilute, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, 6 choyl, alkane Oxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl, -C(0)0R15, -0C(0)R15, -0(CH2 nC(0)0R15, -(CH2)„C(0)0R15, -C(0)R15, -NHC(0)R15, -S(0)pR15, -nr16r17, -〇c(o)nr16r17, Substituting a substituent of -c(0)nr16r17 or -s(0)0NR16R17; or R and R together with a carbon atom to which they are bonded form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aromatic The base or heteroaryl is further optionally one or more selected from the group consisting of halogen, hydroxy, cyano, decyl, decyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl Base, heteroaryl, -C(0)0R15, -0C(0)R15, -〇(CH2)nC(〇)〇R15, -(CH2)nC(0)0R15, -C(0)R15,- Substituted by a substituent of NHC(0)R15, -s(〇)pRi5, -NR16R17, -0C(0)NR16R17, -C(0)NR16R7 or -S(0)0nr16r17; R12 is selected from a hydrogen atom, Halogen, thiol, argyl, decyl, alkoxy, alkyl, dialkyl, alkynyl, J sulphonyl, heterocyclyl, aryl, heteroaryl, -C(0)0R15, -0C ( 0) R15, -0(CH2)nC(〇)〇R15, broad-(CH2)nC(0)0R15, -C(0)R15, -NHC(〇)r15, _s(〇) ri5 -nr16r17,- Oc(o)nr16r17, -C(0)NR16R17 or -s(0)(10)r16r17, wherein the oxy group, alkyl group, ring The alkyl group, heterocyclic group, aryl group or heteroaryl group is further required to be further selected from one or more selected from the group consisting of halogen, thiol, sulfonyl, S-alkyl alkoxy, alkyl, cycloalkyl, heterocyclic, aromatic Base, heteroaryl, two 95255 7 201242964 -0C(0)R15, -0(CH2)nC(0)0R15, -(CH2)nC(0)〇R15, one C(〇)R15, -NHC(0 Substituting a substituent of R15, -S(0)pR15, -NR16R17, -〇c(0)NR16R17, -C(0)NR16R17 or -S(0)0NR16Rn; R13 and R14 are each independently selected from alkyl or Halogen, wherein the alkyl group is further substituted by one or more substituents selected from the group consisting of dentate, hydroxyl, cyano or nitro; R15 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, and an aromatic group. Or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy or oxy Substituted by a substituent; R16 and R17 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group wherein the alkyl group, the alkoxy group, Cycloalkyl, heterocyclic, aryl or heteroaryl Further to be one or more selected from the group consisting of dentate, hydroxyl, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, _C(0)0R15, -〇 C(0)R15,-0(CH2)nC(0)0R15, -(CH2)nC(0)0R15, -C(0)R15, -NHC(0)R15, -S(〇)pR15, -NRI8R19 Substituting a substituent of -C(0)NR18R19, -c(o)nr18r19 or -S(0)0NRl8R19; or R16 and R17 form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group Containing one or more N, hydrazine or S(0)P heteroatoms, and the heterocyclic group is further protected by one or more halogens, trans-, cyano, nitro, alkoxy, alkyl, naphthene as needed Base, heterocyclic group, aryl group, heteroaryl group, hydroxyalkyl group, -C(0)0R15, -〇C(〇)R15,-0(CH2)nC(0)0R15, -(CH2)„C( 0) 0R15, -C(0)R15, -NHC(0)R15, _S(0)PR15, 8 95255 201242964 -NR18R19, -〇c(〇)nr18r19, -C(0)NR18R1U(0)0NR18R19 Substituted; R18 and R19 are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is selected from 1, 2 or 3; n is selected from 1, 2 or 3 ; and Ρ selected from 0 1 or 2. 3. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar is selected from a 5-membered or 6-membered heteroaryl group. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as described in the third aspect of the patent, wherein Ar is a pyrrolyl group or a pyridyl group. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1, wherein R4 and R5 are selected from an alkyl group or an aryl group. 6. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to the scope of claim 1, wherein R4 and R5 together with the carbon atom to be bonded form a cyclopropyl group. A compound represented by the formula (I) according to the first aspect of the invention, wherein R6 is a hydrogen atom. The compound represented by the formula (I) described in the first paragraph of the patent range is suitable for use as a hydrogen atom or a functional element. The compound of the formula (I) described in the first aspect of the patent scope of claim 1 wherein L is selected from -(CH2)m-, and ra is the first item of the patent range of a compound, a pharmaceutically acceptable salt of the formula (I), wherein the compound is selected from the group consisting of: 9 95255 201242964 10 95255 201242964 11 95255 201242964 12 95255 201242964 13 95255 201242964 14 95255 201242964 OH ΝΗ 11. A compound of the formula (A) or a pharmaceutically acceptable salt thereof as described in claim 1 wherein the compound of the formula (I) is in the form of a free or pharmaceutically acceptable acid addition salt. The acid addition salt includes hydrochloride, hydrogen &gt; stinate, sulfonate, sulfate, phosphate, maleate, malate, citrate, acetate or trifluoroacetate . 12. A compound of the formula shown in the formula Or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is present in the form of a free or pharmaceutically acceptable acid addition salt, which is a hydrobromide salt and a hydrochloride salt. A compound represented by the formula (A) or a pharmaceutically acceptable salt thereof as described in claim 1 wherein the salt of the compound is selected from the group consisting of: 15 95255 201242964 16 95255 201242964 17 95255 201242964 18 95255 201242964 19 95255 201242964 20 95255 201242964 14. A process for the preparation of a compound of the formula (I), which process comprises: a compound of the formula (IA) or a compound of (IB) Reaction with a compound of the formula (1C) to give a compound of the formula (I); Wherein: X is selected from halogen; 21 95255 201242964 wherein L, Y, R1 to R11 are as defined in claims i to 8 of the patent application. A method for producing a compound of the formula (1) as described in claim 14, wherein X is a gas atom or a bromine atom. 16. A compound of the formula (ία) or (IB) or a pharmaceutically acceptable salt thereof, which is used as a compound for the preparation of a compound of the formula (I), (ΙΑ) (IB) wherein R1, R2, R3 and Y are as defined in the scope of the patent application; R4 and R5 are each independently selected from the group consisting of cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, Aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is further optionally selected from one or more selected from the group consisting of dentate, hydroxyl, nitro, cyanide Base, alkyl, aryl, heteroaryl, -C(0)0R15, -0C(0)R15, -〇(CH2)nC(〇)〇Ri5, -(CH2)nC(0)0R15 ' -C (0)R,5 &gt; -NHC(0)R15 . -S(〇)pr15 . -nr16r17, -oc(o)nr16r17, -c(o)nr16r17 or -S(0)0nr16r17 substituted Or 'R4 and R5 together with the carbon atom to which they are attached form a cycloalkyl group, wherein the cycloalkyl group is further selected from one or more selected from the group consisting of dentate, thiol, nitro, cyano, alkyl, and oxygen. Substituted by a substituent of a cycloalkyl group or a heterocyclic group; 95255 22 201242964 R6 is selected from the group consisting of a hydrogen atom, a thiol group, a alkyl group, a silk group, a cycloalkyl group, an aryl group, a heteroaryl group, -c_Rl5, _c(9)Rl5 or c(9)nr16r17, the alkyl, methoxy, cyclo, aryl or hetero-filaments are required to enter 4 Substituted by a plurality of substituents selected from the group consisting of a self group, a thiol group, a sulfonyl group, a cyano group, a decyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group; and R15 is selected from a hydrogen atom, a alkyl group, and a cyclofilament. , a heterocyclic, aryl or heteroaryl group wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further subjected to one or more selected from the group consisting of money, thiol and cyano Substituted with a substituent of an alkoxy group, an alkoxy group or an alkyl group; R and R are each independently selected from a hydrogen atom, a hydroxyl group, a alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Wherein the alkyl group, the alkoxy group H group, the heterocyclic group, the aryl group or the heterologous group are further selected from one or more selected from the group consisting of a self group, a thiol group, a cyano group, a 35 group group, an alkoxy group, and a alkyl group. , cycloalkyl, heterocyclic, aryl, heteroaryl, _c(〇)〇Rl5, -〇C(0)R15,-0(CH2)„C(0)0R15, —(ch2)„C( 0) 0R15, -C(〇)R15, -NHC(〇)R15, -S(〇)pR15, -Nr18r19, _〇c(〇)nr18r19, -c(o)nr18r19 or -S(〇)〇NR18Ri9 Substituted by a substituent; or, R and R17 form a heterocyclic group with a nitrogen atom to which they are bonded, wherein the heterocyclic group contains one or a plurality of N, hydrazine or s(〇)p heteroatoms, and the heterocyclic group is further protected by one or more halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocycle as needed Base, aryl, heteroaryl, hydroxyalkyl, -C(0)0R15, -0C(8)R15, -〇(cn2)n(X〇)OR15, (CH2)nC(〇)〇R15, -C(0) Substituting R15, -NHC(0)R15, -S(〇)pR15, NR18R19, -〇C(〇)NR18R19, -c(0)nr18r19 or -S(0)0NR18!^ 95255 23 201242964 R and R are each independently selected from a hydrogen atom, a dentate, a decyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; η is selected from 1 ' 2 or 3; and Ρ is selected from 0, 1 or 2 . The compound of the formula (10) or ((8) or a pharmaceutically acceptable salt thereof as described in claim 16 of the patent application, which is an intermediate for the preparation of a compound of the formula (R), wherein R1, R2, R3 And γ are as defined in the scope of the patent application; R4 and R5 are each independently alkyl or aryl; or R4 and R5 together with the carbon atom to which they are bonded form a cyclopropyl group; R6 is a nitrogen atom. A compound of the formula (ΙΑ) or (ΙΒ) according to the invention of claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 19. A method of preparing a compound of the formula (ΙΑ) or (ΙΒ), the method comprising: 24 95255 201242964 R3 R4 R5 reacting a compound of the formula (I 11) with cuprous cyanide in the presence of a catalyst to obtain a compound of the formula (IA) or (IB); R3 (IV) Alternatively, reacting a compound of the formula (IV) with a Grignard reagent to obtain a compound of the formula (JA) or (IB); (V) Alternatively, reacting a compound of the formula (v) with concentrated aqueous ammonia to obtain a compound of the formula (IA) or (IB); Alternatively, the compound of the formula (VI) can be reacted in water to give a compound of the formula (IA) or a compound wherein R1, R2, R3, R4, R5 and Y are as defined in the first aspect of the patent application. 2. A process for the preparation of a compound of the formula (10) or (10) according to claim 19, wherein the catalyst is cuprous iodide. 95255 25 201242964 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) as described in claim 1 of the patent application, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier . A use of the compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the invention of claim 3, which is for use in the preparation of a calcium ion transport inhibitor. 23. The use of the pharmaceutical composition of claim 21 for the preparation of a calcium ion transport inhibitor. A use of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as described in the scope of the patent application of the invention, which is used for the preparation of a thrombin receptor antagonist. 25. The use of the pharmaceutical composition of claim 21 for the preparation of a thrombin receptor antagonist. 26. The use of claim 24, wherein the thrombin receptor antagonist is a PAR1 receptor antagonist. 27. The use of claim 25, wherein the thrombin receptor antagonist is a PAR1 receptor antagonist. The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, for the preparation of a platelet aggregation inhibitor. 29. The use of the pharmaceutical composition according to claim 21, which is for the preparation of platelet aggregation inhibition, which is represented by the general formula (I) described in claim 1 Use of a compound or a pharmaceutically acceptable salt thereof for the preparation of a smooth muscle cell thickening 26 95255 201242964 inhibitor. 31. Use of the pharmaceutical composition according to claim 21, which is for the preparation of a smooth muscle cell proliferation inhibitor. The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect of the patent application, for the preparation of a medicament for treating a disease associated with a thrombin receptor. 33. Use of the pharmaceutical composition of claim 21 for the preparation of a medicament for treating a thrombin receptor-related disease. 34. The use of claim 32, wherein the thrombin receptor-related disease is selected from the group consisting of thrombosis, restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, pan Intravascular blood coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological diseases and/or malignant tumors. 35. The use of claim 33, wherein the thrombin receptor-related disease is selected from the group consisting of thrombosis, blood vessel restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart Disease, generalized intravascular fluid coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological diseases and/or malignant tumors. 27 95255 201242964 IV. Designated representative map: There is no schema in this case (1) The representative representative figure in this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: L ο^ΑΓ 3 95255